complementary and alternative therapies as add-on to pharmacotherapy for mood and anxiety disorders:...
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Journal of Affective Disorders 150 (2013) 707–719
Contents lists available at ScienceDirect
Journal of Affective Disorders
0165-03http://d
n CorrE-m
journal homepage: www.elsevier.com/locate/jad
Review
Complementary and alternative therapies as add-on topharmacotherapy for mood and anxiety disorders: A systematic review
Arun V. Ravindran a,b,n, Tricia L. da Silva b,c
a Department of Psychiatry, University of Toronto, 250 College Street, Toronto, Ontario, Canada M5T 1R8b Division of Mood and Anxiety Disorders, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, Ontario, Canada M6J 1H4c Institute of Medical Science, University of Toronto, 1 King's College Circle, Room 2374, Toronto, Ontario, Canada M5S 1A8
a r t i c l e i n f o
Article history:Received 22 January 2013Received in revised form22 March 2013Accepted 17 May 2013Available online 12 June 2013
Keywords:Anxiety disordersAugmentationCombinationComplementary and alternative medicineDepressive disordersSystematic review
27/$ - see front matter & 2013 Elsevier B.V. Ax.doi.org/10.1016/j.jad.2013.05.042
esponding author. Tel.: +1 416 979 6933; fax:ail address: [email protected] (A.V. Rav
a b s t r a c t
Background: Depressed and anxious patients often combine complementary and alternative medicine(CAM) therapies with conventional pharmacotherapy to self-treat symptoms. The benefits and risks ofsuch combination strategies have not been fully evaluated. This paper evaluates the risk-benefit profile ofCAM augmentation to antidepressants in affective conditions.Methods: PubMed was searched for all available clinical reports published in English up to December2012. Data were evaluated based on graded levels of evidence for efficacy and safety.Results: Generally, the evidence base is significantly larger for depression than for anxiety disorder.In unipolar depression, there is Level 2 evidence for adjunctive sleep deprivation (SD) and Free andEasy Wanderer Plus (FEWP), and Level 3 for exercise, yoga, light therapy (LT), omega-3 fatty acids,S-adenosylmethionine and tryptophan. In bipolar depression, there is Level 1 evidence for adjunctiveomega-3s, Level 2 for SD, and Level 3 for LT and FEWP. In anxiety conditions, exercise augmentation hasLevel 3 support in generalized anxiety disorder and panic disorder. Though mostly well-tolerated, thesetherapies can only be recommended as third-line interventions due to the quality of available evidence.Limitations: Overall, the literature is limited. Studies often had methodological weaknesses, with littleinformation on long-term use and on potential drug–CAM interactions. Many CAM studies were notpublished in English.Conclusions: While several CAM therapies show some evidence of benefit as augmentation in depressivedisorders, such evidence is largely lacking in anxiety disorders. The general dearth of adequate safety andtolerability data encourages caution in clinical use.
& 2013 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7081.1. Caveat. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7083. Results and discussion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
3.1. Physical therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 708
3.1.1. Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7103.1.2. Yoga . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7113.1.3. Light therapy (LT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7113.1.4. Sleep deprivation (SD) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7123.1.5. Acupuncture. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7123.2. Herbal remedies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
3.2.1. Free and Easy Wanderer Plus (FEWP). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7133.3. Nutraceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 713
3.3.1. Omega-3 fatty acids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7133.3.2. S-adenosylmethionine (SAM-e). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7133.3.3. Dehydroepiandrosterone (DHEA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7143.3.4. Tryptophan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 714ll rights reserved.
+1 416 260 4171.indran).
A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719708
3.3.5. Folate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7143.3.6. Inositol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7143.3.7. N-acetylcysteine (NAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
4. Conclusions and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715Role of funding source . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 715
Table 1Criteria for levels of evidence and lines of treatment.
Levels of evidence Criteria
Level 1 Meta-analysis or replicated double-blind (DB), randomizedcontrolled trial (RCT) that includes a placebo condition
Level 2 At least one DB–RCT with placebo or active comparisoncondition
Level 3 Prospective uncontrolled trial or case series or high qualityretrospective studies
Level 4 Anecdotal reports or expert opinion
Lines of treatment CriteriaFirst line Level 1 or level 2 evidence plus clinical supportSecond line Level 3 evidence or higher plus clinical supportThird line Level 4 evidence or higher plus clinical supportNot recommended Level 1 or level 2 evidence for lack of efficacy
1. Introduction
Epidemiological studies have consistently shown that depres-sive and anxiety disorders are among the most common mentalillnesses. The 1-year prevalence of depressive illness ranges from4% to 11% worldwide, while that of anxiety disorders is 3% to 18%globally (Alonso, 2007; WHO, 2000).
Though pharmacotherapy is generally the first line of treat-ment for depression and anxiety, it has limitations. Many patientscontinue to be symptomatic despite adequate treatment, and inspite of several antidepressant trials, including combinations ofdrugs (Rush et al., 2004; Yonkers et al., 2003). Their side effectsand the high costs associated with medication use can also be adeterrent to compliance (Sajatovic et al., 2011; Zivin et al., 2009).
Complementary and alternative medicine (CAM) therapies areinterventions and products that are perceived to be as effective asconventional pharmacotherapy, but more natural and economical,with fewer side effects and available without need of prescription(Andreescu et al., 2008; Ravindran et al., 2009). They includephysical therapies (e.g. exercise, acupuncture), nutraceuticals(i.e. dietary and nutritional supplements such as vitamins andminerals) and herbal remedies (i.e. plants and plant extracts).An ever-growing number of patients with depression and anxietyreport using CAM therapies to treat their symptoms, often inaddition to conventional medications, and usually without med-ical supervision (Wahlström et al., 2008).
Clinical experience with CAM agents is relatively limited, butpatient use of these agents is increasing significantly. It is thereforeof value to evaluate the benefits and risks of their use as adjunct topharmacotherapy. This paper will review the evidence for thesafety and efficacy of established CAMs as augmentation orcombination with medication for mood and anxiety disorders.Only those CAMs that have a reasonable body of publishedresearch, thus warranting clinical consideration of their use, willbe evaluated. “Augmentation” describes the addition of an agent toexisting antidepressant or anxiolytic treatment; “combination”describes the concurrent use of two or more agents with indivi-dual antidepressant or anxiolytic effects; “add-on” describes eitherstrategy (Lam et al., 2009).
1.1. Caveat
This review does not suggest that CAM therapies should beconsidered first when managing treatment-refractory patients.For patients who are partially or completely non-responsive tofirst-line psychotropics, addition of evidence-based pharmacother-apy (e.g. lithium, atypical antipsychotics) or psychotherapies(e.g. cognitive-behaviour therapy, interpersonal therapy) shouldbe considered first (Lam et al., 2009; Parikh et al., 2009).
2. Methods
A search of the psychiatric literature, using PubMed, wasconducted for all articles relating to the use of physical therapies,
herbal remedies and nutraceuticals as augmentation to medicationin mood and anxiety disorders and published in English up toDecember 2012. The disorders covered in this review include:major depressive disorder (MDD), dysthymia, psychotic depres-sion, treatment resistant depression (TRD), chronic depression,bipolar disorder, seasonal affective disorder, generalized anxietydisorder (GAD), panic disorder (PD), obsessive-compulsive disor-der (OCD), social anxiety disorder (SAD) and post-traumatic stressdisorder (PTSD). Study results were evaluated using the standardcriteria for considering the strength of evidence for efficacy andtolerability (see Table 1). Data from randomized, controlled trials(RCTs) and meta-analyses for the CAMs that showed the strongestevidence (Levels 1 or 2) are summarized in Tables 2–4.
3. Results and discussion
CAM therapies were used as adjunct to a range of psychotro-pics, such as selective serotonin reuptake inhibitors (SSRIs),selective norepinephrine reuptake inhibitors (SNRIs), tricyclicantidepressants (TCAs), atypical antipsychotics (AAPs), monoa-mine oxidase inhibitors (MAOIs), mood stabilizers, andbenzodiazepines.
3.1. Physical therapies
Physical therapies encompass physical practices, such as exer-cise and yoga, and non-invasive biological treatments, such aslight therapy and acupuncture. While popular culture perceivesmost physical therapies as aids to improve physical fitness andrelieve stress, some (e.g. light therapy) are known mainly for theirbenefits to mood.
Table 2Evidence for sleep deprivation as augmentation for depressive disorders.
Study Type N Duration Agent Comparator Efficacy resultsn
Eichhammer et al., 2002 RCT MDD¼15 1 week Existing psychotropics+partial SD+active rTMS
Existing psychotropics+partial SD+sham rTMS
Partial SD+active rTMS4partial SD+sham rTMS (po0.001).Bipolar depression¼5
Giedke et al., 2003 RCT MDD¼37 1 week Existing psychotropics+total SD Existing psychotropics+latepartial SD
Total SD4partial SD (p¼0.008),but the degree of superiority was small.Bipolar depression¼2
Gorgulu and Caliyurt, 2009 RCT MDD¼41 6 weeks Sertraline TSD+sertraline TSD+sertraline4sertraline (po0.001).
Kreuzer et al., 2002 RCT Unipolar depression¼37 1 week Existing antidepressants+total SD+active rTMS
Existing antidepressants+total SD+sham rTMS
No group differences.
Reynolds et al., 2005 RCT MDD¼80 2 weeks Total SD+paroxetine Paroxetine No group differences.Total SD+placebo
Tuunainen et al., 2004 Meta-analysis Total¼20 non-seasonal depression(unipolar and bipolar patient samples)
1−4 weeks Bright LT+SD Control treatments Combination beneficial onlyin SD responders (po0.05).Existing psychotropics+bright LT+SD Existing psychotropics+control treatments
Monotherapy¼2Augmentation¼18
Wu et al., 2009 RCT Bipolar depression¼49 7 weeks Existing psychotropics Existing psychotropics+totalSD+bright LT+SPA
Total SD+bright LT+SPA augmentation4medication alone (po0.05).
n Results statistically significant at po0.05.
Table 3Evidence for FEWP as augmentation for depressive disorders.
Study Type N Duration Agent Comparator Efficacy resultsn
Qin et al., 2011 Meta-analysis Total¼14MDD¼7 4–12 weeks FEWP Placebo or psychotropics FEWP4placebo (po0.00001) and¼psychotropics.Bipolar depression¼2 Existing psychotropics+FEWP Existing psychotropics FEWP+medication4psychotropics
alone (po0.009).Neurotic depression¼1Post-partum depression¼2Depression and medical illness¼2
Monotherapy¼6Combination¼8
Zhang et al., 2007a DBRCT Total¼235 12 weeks CBZ+FEWP CBZ+placebo Depression: CBZ+FEWP4CBZ+placebo (p¼0.032) and4placebo alone (po0.001). CBZ+placebo4placebo alone (p¼0.044).
Bipolar depression¼124Bipolar mania¼111 Placebo Mania: CBZ+FEWP¼CBZ+placebo and4placebo alone (p≤0.012). CBZ+placebo4placebo (p≤0.012).
Zhang et al., 2007b DBRCT Total¼188 26 weeks CBZ+FEWP CBZ+placebo CBZ+FEWP¼CBZ+placebo for continued improvement.CBZ+FEWP4CBZ+placebo for discontinuation (p¼0.009).(Continuation phase of
Zhang et al., 2007a)Bipolar depression¼93Bipolar mania¼84
Zhang et al., 2012a Meta-analysis Total¼26 4–12 weeks FEWP Psychotropics FEWP¼medication.Unipolar depression¼26 Existing psychotropics+FEWP Existing psychotropics FEWP+medication4medication alone (po0.0007).Monotherapy¼8Augmentation¼16
n Results statistically significant at po0.05.
A.V.R
avindran,T.L.daSilva
/Journal
ofAffective
Disorders
150(2013)
707–719
709
Table
4Ev
iden
ceforOmeg
a-3fattyacidsas
augm
entation
fordep
ressivedisorders.
Study
Type
NDuration
Age
nt
Comparator
Effica
cyresu
ltsn
Dep
ression
Bloch
andHan
nestad,2
012
Meta-an
alysis
Total¼
134–
16wee
ksOmeg
a-3fattyacids
Placeb
oNogrou
pdifferences.
Sign
ificantheterog
eneity
andpublicationbias
noted
.MDD¼13
Existingpsych
otropics+
omeg
a-3
Existingpsych
otropics+
placebo
Mon
otherap
y¼7
Augm
entation
¼8
Kragu
ljac
etal.,20
09Meta-an
alysis
Total¼
134–
16wee
ksEx
istingpsych
otropics+
omeg
a-3
Existingpsych
otropics+
placebo
Omeg
a-34
placebo
forunipolar
andbipolar
dep
ression
(p¼0.07
),bu
tnot
man
ia(p
¼0.31
).Sign
ificant
heterog
eneity
ofstudieswea
kenresu
lts.
Unipolar
dep
ression¼8
Bipolar
disorder
¼5
Mon
otherap
y¼0
Augm
entation
¼13
Linan
dSu
,2007
Meta-an
alysis
Total¼
104–
16wee
ksOmeg
a-3fattyacids
Placeb
oOmeg
a-34
placebo
fordep
ressivedisorders
(p¼0.002
),bu
tpublicationbias
andheterog
eneity
wea
kenresu
lts.
Unipolar
dep
ression¼7
Existingpsych
otropics+
omeg
a-3
Existingpsych
otropics+
placebo
Bipolar
dep
ression¼3
Mon
otherap
y¼1
Augm
entation
¼9
Mon
tgom
eryan
dRichardson,2
008
Meta-an
alysis
Total¼
5(bipolar
dep
ression)
4–52
wee
ksEx
istingpsych
otropics
+om
ega-3fattyacids
Existingpsych
otropics+
placebo
Omeg
a-34
placebo
forbipolar
dep
ression
( po
0.04
).Nogrou
pdifferencesforman
ia.
Augm
entation
¼5
Sarris
etal.,20
12Meta-an
alysis
Total¼
6(bipolar
dep
ression)
4–16
wee
ksEx
istingpsych
otropics
+om
ega-3fattyacids
Existingpsych
otropics+
placebo
Omeg
a-34
placebo
forbipolar
dep
ression
(po
0.02
9).N
ogrou
pdifferencesforman
ia.
Augm
entation
¼6
nRe
sultsstatistically
sign
ificantat
po
0.05
.
A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719710
3.1.1. ExerciseExercise has been evaluated in both aerobic (sustained, exer-
tive) and non-aerobic forms. Its antidepressant action has beenproposed to derive from its positive effect on neurogenesis(notably through hippocampal growth and increased expressionof brain-derived neurotrophic factor (BDNF), B-endorphins,vascular endothelial growth factor and serotonin) (Lucassenet al., 2010) and reduced inflammation and oxidative stress(Eyre and Baune, 2012). Exercise is also noted to increase in endo-cannabinoid and atrial natriuretic peptide (ANP) levels (Dietrich andMcDaniel, 2004; Ströhle et al., 2006) and modulate stress reactivitythrough effects on hypothalamic-pituitary adrenocortical (HPA) axisactivity and cortisol production (Lucassen et al., 2010).
There are at least 10 studies in the literature on the use ofadjunctive exercise for unipolar depression. An early open trialreported exercise augmentation beneficial for depression andanxiety in patients with various psychiatric conditions, but onlydepressive improvement was maintained at one-year follow-up(Martinsen et al., 1989b). Other small open trials have also foundadjunctive exercise beneficial for MDD (e.g. Dimeo et al., 2001;Trivedi et al., 2006). However, several RCTs have found no groupdifferences between exercise add-on and exercise and/or medica-tion alone in unipolar depressed patients (Blumenthal et al., 1999;Mota-Pereira et al., 2011; Oeland et al., 2010; Veale et al., 1992:Study 1). Interestingly, in one of these studies, onset of improve-ment was fastest with medication alone (Blumenthal et al., 1999),but at 6-month follow-up, depression was lower and relapse andremission higher with exercise alone (Babyak et al., 2000).Preliminary results from an ongoing RCT have also suggested thesuperiority of exercise as add-on to antidepressants alone insevere MDD (Schuch et al., 2011). Among RCTs evaluating exerciseagainst other non-medication interventions as augmentation forunipolar depression, adjunctive exercise was found superior tooccupational therapy (Martinsen et al., 1985) and comparable tohealth education (Mather et al., 2002). Comparisons of aerobic andnon-aerobic exercise add-on have had mixed results, with nogroup differences noted in two RCTs (Martinsen et al., 1989a; Vealeet al., 1992: Study 2), but aerobic exercise reported superior in athird smaller RCT (Knubben et al., 2007).
In bipolar disorder, a small retrospective chart review foundthat depression and anxiety improved significantly among bipolarinpatients (depressed or manic) who participated voluntarily in anadjunctive exercise program, though overall clinical improvementdid not differ from non-participants (Ng et al., 2007). In addition,exercise augmentation was found beneficial in a small open trial(Dimeo et al., 2001) and in a small RCT (Knubben et al., 2007), bothwith mixed unipolar and bipolar depressed samples.
In anxiety disorders, exercise augmentation improved anxietysymptoms during acute treatment (though not sustained at 1-yearfollow-up) in an early open trial described previously (Martinsenet al., 1989a, 1989b), but had no impact on GAD or PD in a laterRCT (Oeland et al., 2010). Another small RCT in GAD with/outco-morbid depression and anxiety disorders found aerobic andnon-aerobic exercise comparably effective and superior as add-onto wait-list control (Herring et al., 2012). In OCD, two small opentrials noted significant benefits with exercise augmentation, whichpersisted at follow-up even if the exercise regime was notmaintained (Brown et al., 2007; Lancer et al., 2007). In PD, exerciseand relaxation training were comparably effective as augmenta-tion and superior to either treatment alone in an RCT (Wedekindet al., 2010).
Exercise, therefore, has Level 3 evidence for use as augmenta-tion in unipolar and bipolar depression, and in GAD, OCD and PD.In unipolar depression, mixed RCT results and positive datacoming from only open trials support its use as only a third-lineadd-on agent. The very small patient samples in the bipolar and
A.V. Ravindran, T.L. da Silva / Journal of Affective Disorders 150 (2013) 707–719 711
OCD studies negate any recommendation at this time, but exercisemay have some utility as a third-line adjunct for GAD and PD.Heterogeneity in exercise forms and treatment regimes also limitinterpretation. However, higher frequency and intensity of exer-cise appear more beneficial (Perraton et al., 2010; Stathopoulouet al., 2006), Though no significant tolerability issues were noted,possible adverse effects include musculosketal pain and/or injury(Hootman et al., 2002), and risk of cardiovascular events insusceptible patients (Thompson et al., 2007). Exercise may alsoimpact lithium levels in bipolar patients (Wright et al., 2009), andtemporarily increase anxiety in those with high anxiety sensitivity(Ströhle, 2009).
3.1.2. YogaYoga has three main components (postures, breathing exercises
and meditation), which are given variable emphasis in the differ-ent yoga forms practiced (da Silva et al., 2009). Its posited role inreducing sympathetic activity, improving parasympathetic drive,normalizing HPA axis activity, and influencing monoaminechanges, may explain its potential effects on mood (Brown andGerbarg, 2005; Streeter et al., 2012). As well, controlled breathing,considered to be the most therapeutic component of yoga, is proposedto activate vagal afferents to autonomic, neuroendocrine, and limbiccircuits, with positive impact on emotion regulation and stressresponsivity (Brown and Gerbarg, 2005; Streeter et al., 2012).
Literature on the use of adjunctive yoga in depressive disordersis not extensive. A recent medium-size meta-analysis concludedthat yoga was an effective adjunct treatment of major psychiatricdisorders, particularly depression and anxiety (Cabral et al., 2011).However, most included studies were monotherapy trials, andseveral recruited patients based only on self-report, which limitthese conclusions. Among depression studies, a small RCT in MDDfound that Sahaj yoga augmentation superior to medication alone(Sharma et al., 2005). Another RCT, with medicated and unmedi-cated unipolar depressed patients, did not report acute treatmentdata, but at 9-month follow-up, noted better remission with Hathayoga+psychoeducation and a trend to higher rates of relapse withpsychoeducation alone (Butler et al., 2008). Small open trials alsoreported Iyengar yoga (Shapiro et al., 2007) and Vinyasa yoga(Uebelacker et al., 2010) significantly effective as add-on forunipolar depression.
There is no published data on the use of yoga as augmentationin bipolar disorder.
The evidence for yoga as augmentation in anxiety disorders iseven sparser. In GAD, an open trial found adjunctive SudarshanKriya Yoga significantly improved anxiety symptoms, but treat-ment was very brief at 5 days (Katzman et al., 2012). In OCD, asmall open trial found Kundalini yoga augmentation beneficial andassociated with reduced medication use; interestingly, unmedi-cated patients did not show symptom improvement and droppedout early (Shanahoff-Khalsa and Beckett, 1996). In a subsequentRCT by the same group, Kundalini yoga meditation add-on wassuperior to relaxation+meditation in OCD (p values not reported);the merged treatment group received an open course of yoga,resulting in significant improvement and reduced medication use(Shannahoff-Khalsa et al., 1999).
The above data suggest that yoga has Level 3 evidence ofbenefit as an adjunctive treatment for unipolar depression, sug-gesting possible third-line use. The evidence of benefit in GAD andOCD is too preliminary to support any recommendations. Metho-dological weaknesses also limit generalizability, while groupdynamics may also have contributed to benefits seen (Ravindranet al., 2009). Though long-term safety data is lacking, reported sideeffects are rare, and have tended to be mild and linked to level ofphysical fitness (Pilkington et al., 2005). Very occasionally,
meditation-induced mania or psychosis has been reported invulnerable patients, as well as single cases of serious adverseeffects such as artery occlusion or lotus neuropathy (see overviewin Pilkington et al., 2005), the latter possibly resulting fromexcessive or incorrect yoga practice.
3.1.3. Light therapy (LT)LT, also described as bright light therapy (bright LT), involves
daily exposure to artificial bright light, usually through the use of afluorescent light box or light-emitting diodes (Ravindran et al.,2009; Tuunainen et al., 2004). LT is thought to influence mood viaimpact on the suprachiasmatic nucleus and melatonin production(which are both involved in circadian rhythm regulation), and onmonoaminergic modulation (Pail et al., 2011).
In seasonal depression, a small RCT found no group differencesbetween add-on with CBT+LT or either treatment alone, butsymptom severity was lowest with CBT+LT and relapse highestwith LT alone at 1-year follow-up (Rohan et al., 2004). Another RCTreported similar response to bright LT, dim light and negative-iontherapy as adjunct in seasonally depressed unipolar and bipolarpatients, though remission was significantly greater with bright LT(Flory et al., 2010).
There have been contradictory findings in non-seasonaldepression, as well, with one systematic review reporting benefitswith adjunctive LT in unipolar and bipolar depression (Even et al.,2008), while two meta-analyses did not (Golden et al., 2005;Tuunainen et al., 2004). In more recent publications, RCTs in MDDnoted the superiority of bright LT to dim light as add-on (Lieverseet al., 2011; Wirz-Justice et al., 2011). Two other RCTs in unipolardepression failed to find such difference, but used self-ratedmeasures and not objective clinical ratings (Lande et al., 2011;Niederhofer and von Klitzing, 2011). Augmentation with earlymorning bright LT was reported superior to late morning brightLT in another RCT in MDD (Dallaspezia et al., 2012).
In bipolar depression, a small RCT found no groups differencesbetween augmentation with bright LT or negative-ion therapy(Dauphinais et al., 2012). Another RCT (described earlier) alsofailed to distinguish between adjunctive bright LT, dim light andnegative-ion therapy in seasonally depressed unipolar and bipolarpatients, though bright LT produced higher remission (Flory et al.,2010). However, open trials have noted positive findings with LTadd-on (Benedetti et al., 2009a) or augmentation with total sleepdeprivation plus LT (Benedetti et al., 2005, 2007, 2009b), with drugresistance a possible influence on response to total SD+LT(Benedetti et al., 2005, 2007).
There are no published studies of LT augmentation in anxietydisorders.
In summary, LT has Level 3 evidence of benefit as augmentationin both seasonal and non-seasonal unipolar depression and bipolardepression. However, methodological weaknesses and sparselong-term efficacy and safety data would suggest its use asthird-line adjunctive treatment only. Many patients relapse uponcessation of LT (Benedetti et al., 2005; Martiny et al., 2006), andother adverse effect include (mild) sleep difficulties, headache, eyeirritation, blurred vision, menstrual irregularities, nausea andagitation (Terman and Terman, 2005). However, no ocular changesor abnormalities were found after either short-term (2–8 weeks)or extended (3–6 years) LT use (Gallin et al., 1995). Induction ofmanic switch or mixed state in vulnerable individuals has beenreported occasionally (e.g. Chan et al., 1994; Sit et al., 2007), andworsening of pre-existing suicidal ideation under ineffectivetreatment conditions appears to explain the rare instances ofreported suicidality (Terman and Terman, 2005). LT-medicationinteraction is also a potential concern, as is increased photosensi-tivity with use of psychotropics (Sohn and Lam, 2004).
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3.1.4. Sleep deprivation (SD)In SD, patients are kept awake for extended periods, with
total sleep deprivation (total SD) lasting up to 40 h, and partialsleep deprivation (partial SD) allowing 3–4 h of sleep per night(Benedetti and Colombo, 2011). In an SD cycle, an SD period isfollowed by a recovery sleep. SD is thought to have multi-modalinfluences on mood, involving impact on HPA axis activity andthyroid hormone levels (Parekh et al., 1998; Vgontzas et al., 1999),and on metabolic and monoaminergic functioning (Benedetti andColombo, 2011; Giedke and Schwarzler, 2002).
Over 60 studies have been reported on SD for depression andthough no meta-analyses are available, systematic reviews havenoted the benefits of SD augmentation in MDD (Morgan and Jorm,2008; Ravindran et al., 2009). Small RCTs (Caliyurt and Guducu,2005; Gorgulu and Caliyurt, 2009) and small open trials (Bernieret al., 2009; Murck et al., 2009; Wiegand et al., 2001) have notedthe benefits of SD (primarily total SD) augmentation in MDD, butwith frequent drop-out due to non-response noted in two ofthe open trials (Bernier et al., 2009; Wiegand et al., 2001).No differences between SD augmentation and either treatmentalone noted in another RCT (Reynolds et al., 2005). One RCT foundtotal SD add-on slightly superior to partial SD in unipolar andbipolar depression (Giedke et al., 2003). Among evaluations of SDversus non-pharmacological comparators as augmentation, asmall RCT found adjunctive partial SD+active rapid transcranialmagnetic stimulation (rTMS) superior to partial SD+sham rTMS inMDD and bipolar depression (Eichhammer et al., 2002). However,a later augmentation RCT in MDD did not distinguish betweentotal SD+rTMS and total SD+sham rTMS (Kreuzer et al., 2002). Inevaluations of SD+LT add-on, a large meta-analysis in unipolar andbipolar depression found it effective only in SD responders(Tuunainen et al., 2004). Small open trials have also reportedbenefits with total SD combined with sleep phase advance (SPA)(a technique in which the patient's sleep cycle is advanced by up to6 h) as add-on in MDD (Berger et al., 1997; Voderholzer et al., 2003),albeit with noticeable drop-out due to non-response and treatmentchallenges (Berger et al., 1997). The combination of total SD+brightLT+SPA was also found effective in MDD and bipolar depression in asmall open trial (Echizenya et al., 2013).
Expert reviews have found SD augmentation effective inbipolar depression, and also suggest that it may elicit strongerresponse in bipolar than unipolar depression (Dallaspezia andBenedetti, 2011; Giedke and Schwarzler, 2002). An RCT (describedearlier) found total SD slightly superior to partial SD in unipolarand bipolar depression, though the bipolar sample was verysmall (Giedke et al., 2003). In comparisons of adjunctive SD tonon-medication augmentors, a small RCT (already reported inthis section) found partial SD+active rTMS superior to partialSD+sham rTMS as augmentation in MDD and bipolar depression(Eichhammer et al., 2002). As also noted earlier, a large meta-analysis found SD+LT add-on beneficial only in SD responders(Tuunainen et al., 2004), but subsequent open trials noted strongerresults (Benedetti et al., 2005, 2007, 2009b). More recently, an RCT(Wu et al., 2009) and a small open trial (Echizenya et al., 2013)found augmentation with total SD+bright LT+SPA significantlyeffective. Small open trials have also offered support for adjunctivetotal SD+SPA (Benedetti et al., 2001; Voderholzer et al., 2003).
There are no published data for SD as augmentation in anxietydisorders.
SD, therefore, has Level 2 evidence for use as augmentation inMDD and bipolar depression (see Table 2). Support for its use asadjunct to medication, when combined with other therapies (LT,SPA, rTMS), is far less robust, though SD+LT shows Level 3 evidencein bipolar depression. Also of note, though reviews find both formsof SD comparably effective, total SD dominates research publica-tions and may thus have clinical preference (Giedke and
Schwarzler, 2002). Lack of robust evidence and practical limita-tions of applying SD (described below), would suggest its use asadjunct only, and as third-line. Although SD may produce rapidbenefit (toa degree comparable to medications), quick relapse followinga recovery sleep and frequent development of tolerance, as wellas patient difficulty with sustaining more than brief treatment,have been noted (Ravindran et al., 2009). Long-term efficacy andsafety data is sparse, but common side effects include headache,sleepiness, fatigue, and occasionally, gastrointestinal symptoms,worsening of depression and elevated mood/(hypo)mania invulnerable patients (Giedke and Schwarzler, 2002).
3.1.5. AcupunctureAcupuncture (ACP) is part of Traditional Chinese Medicine
(TCM) and is a treatment in which fine needles are inserted intothe skin at specific body points (acupoints) to produce therapeuticbenefits; TCM theory suggests that manual or electrical stimula-tion of these needles helps to normalize ‘qi’ or energy flow withinthe body and rectify imbalances that may contribute to physical ormental illness (Gunn, 2005). In current forms of ACP, traditionalmanual ACP (M-ACP) uses manual manipulation of acupunctureneedles, electroacupuncture (E-ACP) passes mild electric currentthrough acupuncture needles, and laser ACP (L-ACP) directs a lowpowered laser on acupoints (Smith et al., 2010). It has beensuggested that ACP impacts the central nervous system by stimu-lating monoamine and endorphin production (Cheng andPomeranz, 1981; Han, 2004), and influencing brain activity, parti-cularly of the limbic region and subcortical structures (Hui et al.,2000; Napadow et al., 2005).
Meta-analyses in MDD have reported either no group differ-ences or inconsistent results for ACP augmentation versus medica-tion alone (Mukaino et al., 2005; Smith et al., 2010; Wang et al.,2008; Zhang et al., 2010). Among more recent trials, RCTs foundE-ACP augmentation comparable to medication alone, but associatedwith faster response (Duan et al., 2009, 2011), while an open trialfound M-ACP add-on beneficial (Yeung et al., 2011). However, RCTshave also reported active ACP and sham ACP equivalent as adjunct(Zhang et al., 2009, 2012b), though response was quicker andlarger (Zhang et al., 2012b) and side effects fewer (Zhang et al.,2009) with active ACP. Meta-analytic comparisons of ACP mod-alities have found M-ACP and E-ACP equally effective (Smith et al.,2010; Stub et al., 2011).
In bipolar disorder, most available studies are published only inChinese and are not reviewed here. Among English publications, asmall RCT found active or sham ACP add-on comparably effectivein (hypo)mania and bipolar depression (Dennehy et al., 2009).An early case series found adjunctive E-ACP generally inferior toECT for bipolar depression and mania, but better tolerated(Kurland, 1976), while a later case report reported ACP add-onbeneficial for mania (Hu, 1996).
In anxiety conditions, an RCT in GAD found M-ACP augmenta-tion superior to medication alone, but inferior to M-ACP alone(Yuan et al., 2007). In OCD, an RCT found M-ACP add-on nodifferent from medication alone, but better tolerated (Feng et al.,2007). In PTSD, an RCT found M-ACP and CBT comparable as adjunctand superior to wait-list, with gains maintained at 3-month follow-up(Hollifield et al., 2007).
To summarize, the findings are promising but poor quality andheterogeneity of published studies preclude definitive recommen-dations for the use of ACP augmentation in unipolar depression,bipolar disorder or anxiety disorders. Notably, sham ACP isthought to produce physiological effects, itself (Zhang et al.,2009), and may explain its comparable efficacy versus activeACP. Long-term efficacy and safety data are lacking, but ACP
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appears well tolerated. Reported mild side effects include bleed-ing, pain and bruising at needling points, as well as drowsiness,fatigue and headache (MacPherson and Thomas, 2005). Infection,seizures, pneumothorax and temporary neuropathy are rare moreserious adverse events, but it has also been noted that risk ofserious side effects with acupuncture is far lower than with manyconventional medical treatments (White, 2004).
3.2. Herbal remedies
Herbal remedies are non-prescription, natural health productsderived from plants and plant extracts, such as leaves, flowers,roots, bark and berries. Available as individual herbal supplements,as well as herbal compounds that incorporate several herbs intoformulations that are thought to have synergistic benefits, they arefrequently used individually or in combination to support generalwellness or resolve symptoms of physical or mental stress. Veryfew herbal remedies have published evidence as add-on for moodand anxiety disorders. It is of note that St. John's wort (hypericumperforatum), the most studied herbal remedy for depression, doesnot have any published data as an adjunctive agent.
3.2.1. Free and Easy Wanderer Plus (FEWP)This 11-ingredient Chinese herbal compound has a long history
of use. It is thought to act on multiple monoaminergic andbenzodiazepine receptors, as well as neurosteroid and cytokinefunction, accounting for its antidepressant and anxiolytic effects(Liao et al., 1995; Mizowaki et al., 2001; Sugiyama et al., 1996).
Large meta-analyses have found FEWP safe and effective asaugmentation in unipolar depression, and better tolerated thanmedication alone (Qin et al., 2011; Zhang et al., 2012a). It is of notethat most of the included studies were published only in Chinese.
In bipolar depression, one meta-analysis reported FEWP effec-tive as add-on, but included data from only two bipolar studies(Qin et al., 2011). Among additional English publications, a 3-armRCT found adjunctive FEWP superior to placebo add-on andplacebo alone for bipolar depression, and also better tolerated,implying that FEWP may reduce medication side effects (Zhanget al., 2007a). The augmentation treatments also improved maniacomparably. In the continuation phase of the study (whichincluded only the augmentation treatments), both groups contin-ued to improve comparably, but drop-out rates were lower withFEWP (Zhang et al., 2007b)
There are no published reports of FEWP as augmentation inanxiety disorders.
Based on the available data, FEWP has significant Level 2evidence of benefit as augmentation agent in both unipolar andbipolar depression (see Table 3), but due to limited clinicalexperience outside its country of origin (as with Jio-zai), andmethodological weaknesses in many studies, it is recommended asonly a third-line adjunctive treatment. Side effects reported withFEWP include mild headache, dizziness, diarrhea, constipation, drymouth and tachycardia (Qin et al., 2011; Zhang et al., 2012a). Long-term efficacy and safety data (in English) is lacking.
3.3. Nutraceuticals
Nutraceuticals (also known as dietary supplements) areconcentrated forms of naturally occurring substances, such asvitamins and minerals. Like herbal remedies, they are categorizedas natural health products that can be used without prescription.They are popularly used for nutritional and health support, bothindividually and in combination.
3.3.1. Omega-3 fatty acidsPolyunsaturated omega-3 fatty acids are involved in multiple
biological systems, including the nervous system. As supplements,they are highly purified estyl esters of eicosapentanoic acid (EPA)or docosahexaenoic acid (DHA) or a combination. Their neurop-sychiatric effects are thought to result from modulation of neuro-nal communication and their impact on monoaminergic neuralsystems (Ross et al., 2007). Low omega-3 levels have been linkedto both depression (Lin et al., 2010) and anxiety (Ross, 2009).
Though omega-3 fatty acids appear beneficial as augmentationagents in unipolar depression in individual studies, several meta-analyses have failed to find robust evidence of benefit (e.g. Blochand Hannestad, 2012; Kraguljac et al., 2009; Lin and Su, 2007).
In bipolar disorder, a systematic review was inconclusive(Turnbull et al., 2008), but meta-analyses have noted the benefitsof omega-3 fatty acid augmentation in bipolar depression, though notin mania (Montgomery and Richardson, 2008; Sarris et al., 2012).These reports noted that effect sizes were larger in smaller studies andmethodological weaknesses were also common.
In anxiety disorders, a small cross-over RCT found no benefit toEPA or placebo augmentation, though EPA was well tolerated(Fux et al., 2004). Similarly, EPA augmentation was no different fromEPA alone in a small open-label case series in PTSD (Zeev et al., 2005).
In conclusion, omega-3 fatty acids have Level 1 evidence ofbenefit as augmentation in bipolar depression, and Level 2 evi-dence in unipolar depression (see Table 4). However, due to theheterogeneity of studies and publication bias noted in bothpopulations, they may be best used as third-line augmentationsfor both conditions. Meta-analytic comparisons of omega-3 for-mulations are suggestive (but not definitive) that EPA may besuperior to DHA or EPA+DHA for depressive disorders (Martinset al., 2012; Ross et al., 2007). There is no current evidence for thebenefit of omega-3 fatty acids in anxiety disorders. Omega-3s aregenerally well tolerated, and side effects reported, such as nauseaand a fishy aftertaste, are mild and rarely lead to discontinuation(Freeman et al., 2010). Omega-3s have also shown cardioprotectivebenefits, but monitoring is recommended when used by patientson anticoagulants or anti-platelet medications, due to increasedbleeding tendencies (Freeman et al., 2010). Risk of hypomania hasbeen noted in a few cases, but no such incidence has beenreported in systematic reviews or meta-analyses in bipolar depres-sion (e.g. Montgomery and Richardson, 2008; Sarris et al., 2012).
3.3.2. S-adenosylmethionine (SAM-e)A naturally occurring body molecule, SAM-e is a derivative of
the amino acid, methionine and functions as a methyl donor inmany biological processes (Alpert et al., 2008). It is thought toboost monoaminergic neurotransmission as its mechanism ofaction (Alpert et al., 2008), but a proposed relationship betweenlow SAM-e levels and depression has not been conclusively proven(Bottiglieri and Hyland, 1994). It is available as an over-the-counterproduct in North America, but requires medical prescription inEurope.
Most reports of SAM-e in depression are as monotherapy.However, an RCT in treatment-resistant major depression (TRD)found SAM-e as adjunct to antidepressants was significantlysuperior to placebo; mild side effects and drop-out due to sideeffects was similar between groups, but drop-out due to lack ofefficacy was higher with placebo (Papakostas et al., 2010). An opentrial of SAM-e augmentation in TRD reported similar efficacy andtolerability (Alpert et al., 2004).
No data was found for SAM-e as augmentation in anxietydisorders.
The limited Level 3 data above offers only preliminary supportfor SAM-e as augmentation in TRD, with recommendation as only
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a third-line strategy. It is generally well-tolerated, but reportedadverse events include nausea, restlessness and diarrhea, and,more rarely, risk of manic induction in vulnerable patients andserotonin syndrome in patients on antidepressants (NaturalStandard, 2013b).
3.3.3. Dehydroepiandrosterone (DHEA)DHEA, a natural adrenosteroid, is a precursor of the sex
hormones, estrogen and testosterone, and is also employed innatural medicine as an anti-aging aid (albeit with undeterminedbenefits) (Bhagra et al., 2008). It is thought to modulate monoami-nergic and glutaminergic neurotransmission, as well as provideneuroprotective and anti-oxidant benefits (Maninger et al., 2009).Both low DHEA (Markianos et al., 2007; Morsink et al., 2007) and highDHEA (Assies et al., 2004; Goodyer et al., 2003) levels have been linkedto depression, but in anxiety, high DHEA levels have been reportedmore consistently (Gill et al., 2008; Hsiao, 2006).
Only one augmentation study in depressive disorders wasfound. In a small RCT, DHEA add-on was superior to placebo inimproving unipolar and bipolar depression and was also welltolerated (Wolkowitz et al., 1999). Of note, only 2 bipolar patientsparticipated in the study.
No published data was found for DHEA as augmentation inanxiety disorders.
There is insufficient evidence to recommend DHEA for thetreatment of depression. Though it is well tolerated, potential sideeffects include acne, hirsuitism, worsening of prostatis andincreased risk of breast cancer, due to its role as a precursor inhormone production, as well as impact on blood clotting, liverdamage, manic induction (Natural Standard, 2013a).
3.3.4. TryptophanThe dietary amino acid, tryptophan, is a precursor of 5-hydroxy
tryptophan (5-HTP) and serotonin (5-HT), and is thus thought toenhance serotonergic neurotransmission through “precursor loading”(Shaw et al., 2002). Formulated as both 5-HTP and l-tryptophan, itrequires medical prescription in Canada and Europe, but is availableover-the-counter in the U.S. Lowmood and cognitive dysfunction havebeen reported with tryptophan depletion in patients vulnerable todepression (Booij et al., 2005; Feder et al., 2011).
Only a few small studies have evaluated tryptophan augmenta-tion in depressive disorders. Two early small RCTs found adjunc-tive 5-HTP superior to placebo in unipolar depression (Aliño et al.,1976; Nardini et al., 1983), with the former noting quicker onset ofaction. A small open trial and a placebo-controlled RCT by onegroup of researchers also found 5-HTP augmentation beneficial inunipolar and bipolar depression, though the RCT also noted thatthe combination did not differ from l-tryptophan alone, andl-tryptophan was itself no different from placebo (Mendlewiczand Youdim, 1980). Of note, a large review found significantmethodological flaws in these early studies (Turner et al., 2006).More recently, a small placebo-controlled RCT found adjunctivel-tryptophan produced early onset of improvement in MDD, butwhich was not sustained to endpoint (Levitan et al., 2000).
There are no published studies of tryptophan as add-on inanxiety conditions.
Thus, the evidence for tryptophan augmentation in depressionis only preliminary (Level 3), supporting only third-line recom-mendations. Despite its role as a serotonin precursor, serotoninsyndrome has rarely been reported with tryptophan use, and therehas been no recurrence of Eosinophilia–Myalgia Syndrome, anoutbreak of which was linked to a single manufacturer and acontaminated batch of tryptophan in the late 1980s (Turner et al.,2006). Side effects reported in studies (e.g. Aliño et al., 1976;
Levitan et al., 2000) were mild and commonly include sedation,dry mouth and gastrointestinal distress.
3.3.5. FolateThe water-soluble B vitamins, of which folate (B9) is one, are
vital to cellular activity and immune and nervous system function-ing. Folate is a key to production of homocysteine, a precursor ofmethionine and S-adenosyl methionine, the latter being a methyldonor involved in neurotransmitter function (Farah, 2009). Theevidence for the association between low folate levels anddepression is mixed, with no definitive conclusions (e.g. Coppenand Bolander-Gouaille, 2005; Kamphuis et al., 2008).
In depressive disorders, small systematic reviews have reportedfolate to be effective and well tolerated as augmentation inunipolar depression (Fava and Michoulon, 2009; Morris et al.,2008). Included in the reviews were early RCTs that noted thebenefits of folic acid or methylfolate over placebo as augmentationin unipolar depression (Coppen et al., 1986; Godfrey et al., 1990),with the caveat that the patient sample in one study was onlymarginally symptomatic and no benefits were seen in bipolarpatients (Coppen et al., 1986). Another RCT found adjunctive folicacid superior to placebo only in female MDD patients (Coppen andBailey, 2000), while an open trial noted significant improvementwith folinic acid augmentation in TRD, but the reported responseand remission rates were low (Alpert et al., 2002). More recently, asmall RCT found adjunctive folinic acid superior to placebo in MDD(Resler et al., 2008), but a small randomized open trial in MDDfound medication alone superior to folic acid augmentation(Basoglu et al., 2009). Tolerability data were not reported in thesestudies. A large retrospective case analysis found l-methylfolate add-on superior to medication alone, and with quicker onset of action andlower drop out due to side effects (Ginsberg et al., 2011).
In bipolar disorder, an early RCT (described previously) foundno benefit to adjunctive folic acid in marginally depressed bipolarpatients (Coppen et al., 1986). A more recent RCT in mania foundfolic acid and placebo comparably effective and tolerable as add-on, with folic acid separating favorably from placebo only at end oftreatment (Behzadi et al., 2009).
There are no published studies of folate as augmentation inanxiety disorders.
Thus, there is only preliminary and inconsistent evidence forfolate as augmentation in unipolar depression, precluding anyrecommendations at this time. Though it appears well toleratedand no drug interactions have been reported, high doses of folateincreases levels of unmetabolized serum folic acids, possiblycontributing to depletion of natural killer cells, monoamines andbrain l-methylfolate, thus worsening depression (Farah, 2009; Favaand Michoulon, 2009). Similarly, high folic acid dosage is linked toincreased depression, sleep difficulties, irritability, hyperactivityand discomfort (Farah, 2009; Lazarou and Kapsou, 2010).
3.3.6. InositolInositol is a carboxylic polyol and glucose isomer that is
sometimes included in the B vitamin family (Taylor et al., 2004).It is a precursor of the cellular secondary messenger system thatmediates neurotransmitter receptor activity and intracellularfunctioning (Taylor et al., 2004). Human studies of the linksbetween low inositol levels and depression have had equivocalresults (Coupland et al., 2005; Levine et al., 1996), while animaldata suggest an association between low inositol and anxiety(Einat and Belmaker, 2001; Kofman et al., 2000).
In depressive disorders, a small meta-analysis in unipolar andbipolar depression (Taylor et al., 2004) that included two smallRCTs in MDD (Levine et al., 1999; Nemets et al., 1999) foundinositol no different from placebo as augmentation for unipolar
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depression, though drop out due to side effects was higher withinositol in one of the studies (Nemets et al., 1999).
Similarly, in bipolar depression, two RCTs also failed to differ-entiate between inositol or placebo add-on (Chengappa et al.,2000; Eden Evins et al., 2006). With the second RCT, though atrend favored adjunctive inositol in the double-blind phase, openlabel continuation with inositol also found only non-significantbenefits (Eden Evins et al., 2006). Interestingly, a small rando-mized open label arm of the Systematic Treatment EnhancementProgram for Bipolar Disorder (STEP-BD) study, found inositoland psychotropics comparably effective as add-on (Nierenberget al., 2006). Inositol was generally well tolerated in these studies(Chengappa et al., 2000; Nierenberg et al., 2006).
In anxiety disorders, a small placebo-controlled RCT (Fux et al.,1999) and a small open trial (Seedat and Stein, 1999) both failed tofind benefits to inositol augmentation (Seedat and Stein, 1999).
In summary, there is insufficient evidence to recommend inositolaugmentation in either depressive or anxiety conditions. Though itusually has good tolerability, serotonin syndrome and symptomexacerbation requiring hospitalization, including (hypo)manic induc-tion, have been reported in some patients (Chengappa et al., 2000;Eden Evins et al., 2006; Levine et al., 1999; Nemet et al., 1999).
3.3.7. N-acetylcysteine (NAC)NAC derives from the amino acid, cysteine, which is the
precursor of a key brain antioxidant, glutathione (Berk et al.,2008). Higher oxidative stress, which is implicated in the patho-physiology of depression, is linked to impaired glutathione meta-bolism (Berk et al., 2008).
In bipolar disorder, a small maintenance RCT found NAC add-onwell tolerated and superior to placebo in improving depression,with a trend to improving mania, as well; however, there were nogroup differences in time to mood episode (Berk et al., 2008).A subsequent two-phase study by the same researchers foundadjunctive NAC beneficial as open label for bipolar depression, butno different from placebo in the double-blind phase (Berk et al.,2011, 2012).
In anxiety disorders, only a single case report noted the benefitof NAC as augmentation in refractory OCD (Lafleur et al., 2006).
There is only Level 3 evidence of benefit for NAC and EMP+ indepressive disorders, but mixed results preclude recommenda-tions. It was generally been well tolerated in published studies, butthe sparse safety data advises caution in its use.
4. Conclusions and future directions
The popularity of CAM therapies among patients with moodand anxiety disorders has stimulated more recent research intothe utility and safety of these agents. However, the overall body ofresearch on CAM therapies remains limited. The literature has alsotended to focus on depressive disorders over anxiety conditions,perhaps reflecting the perceived differential clinical and functionalimpact of the disorder categories. The literature on CAM therapiesthat evaluates their benefits as adjunctive agents to antidepres-sants is even sparser, as confirmed by this review.
In summary, the available evidence would suggest the follow-ing: As adjunctive treatment in unipolar depression, is the stron-gest evidence (Level 2) is for SD and FEWP, followed by Level3 evidence for the exercise, yoga, LT, omega-3 fatty acids, SAM-e,and tryptophan. LT also has Level 3 evidence as add-on in seasonaldepression. In bipolar depression, the strongest evidence (Level 1)is for adjunctive omega-3 fatty acids, followed by Level 2 evidencefor SD, and very preliminary Level 3 evidence for LT and FEWP. Inanxiety conditions, only exercise has been found to have somebenefit (Level 3) in GAD and PD. There is insufficient or negative
evidence for augmentation use of acupuncture, folate, inositoland NAC.
Due to the sparse data, frequent methodological weaknesses ofstudies and limited clinical experience, the evidence for the CAMtherapies reviewed here is generally insufficient evidence toprovide a definitive recommendation. At most, they can besuggested as third-line strategies. As well, as stated previously,any use of CAM therapies should follow only after a trial of first-line augmenting interventions, such as other antidepressants,atypical antipsychotics or mood stabilizers, and evidence-basedpsychotherapies.
However, it is encouraging that the basic physiological mechan-isms of action attributed to the CAM therapies reviewed here seemto mirror those of established pharmacological agents, such asimpact on neuroplasticity, neurogenesis, and monoaminergic,glutaminergic and HPA axis activity. It is also noteworthy thatthe published evidence indicates that CAM therapies are generallywell tolerated, and that some CAM agents may help to alleviateside effects associated with conventional medications. Thus, thisreview provides a rationale for the further exploration of CAMtherapies as augmentation to antidepressants in larger, placebo-controlled RCTs, for both acute and maintenance treatment.
Role of funding sourceThis manuscript was prepared independently without any funding support.
Conflict of interestThe authors have no actual or potential conflicts of interest to disclose.
AcknowledgmentsNone.
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