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1 Introduction

Depressive and anxiety disorders are the most common psychiatric conditions found in the general population. Depressive disorders, which encompass unipolar depression and bipolar disorder, have an estimated 12-month prevalence of up to 11%, while anxiety conditions, which include generalized anxiety disorder (GAD), panic disorder (PD), obsessive-compulsive disorder (OCD), social anxiety disorder (SAD) and post-traumatic stress disorder (PTSD), have a 1 year prevalence of up to 18% [1, 2].

Despite the wide range of pharmacological and psychological interventions available for depressive and anxiety conditions, up to a quarter of patients show partial or no response even with adequate treatment, and for many, a chronic course of illness is common [3–5]. Side effects (with medications), time and accessibility (with psychotherapy), and cost factors can be further obstacles to patient compliance and full recovery [6, 7]. These limitations are frequently cited among the reasons that many patients turn to complementary and alternative medication (CAM) therapies for symptom relief, under the perception that these ‘natural’ therapies are more effective, affordable and tolerable [8–10]. It is quite common for patients to use CAM therapies without medical supervision, and while also receiving conventional treatments [11, 12].

CAMs fall into three main categories: physical therapies (e.g. exercise, acupuncture), nutraceuticals (i.e. dietary and nutritional supplements such as vitamins and minerals) and herbal remedies (i.e. plants and plant extracts) [9]. Although the data on the utility of such treatments is not as extensive as that for more conventional treatments, the field of research is growing in response to patient interest and use. Published data suggests that several CAMs have shown some benefits in depression and anxiety, both as monotherapy and as adjunctive treatments to pharmacotherapy. As the benefits and risks of physical therapies have been reviewed extensively and recently elsewhere [e.g. 13–15], this chapter will focus on the data relating to nutraceuticals and herbal remedies as augmentation or combination with conventional treatments for mood and anxiety disorders.

A search of the psychiatric literature, using PubMed, was conducted for all articles relating to the use of herbal and dietary supplements as augmenting agents in mood and anxiety disorders and published in English up to May 2012. The range of disorders covered in this review include: Major depressive disorder (MDD), dysthymia, psychotic depression, treatment resistant depression (TRD), chronic depression, bipolar disorder, generalized anxiety disorder (GAD), panic disorder (PD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). Information was summarized on the design, methods and outcomes of these studies. Study results were evaluated using the standard methodology for considering the strength of evidence for efficacy and tolerability.

The data reviewed below on herbal and dietary supplements used as augmenting or combination agents in depressive and anxiety disorders is also summarized in Tables 11.1, 11.2, 11.3 and 11.4. In published literature, “augmentation” refers to the addition of an agent to an existing treatment regime, usually antidepressants [65]. “Combination” refers to the concurrent use of two or more agents, who individually have antidepressant/anti-anxiety effects on their own, as treatment. “Add-on” refers to either strategy. The studies described below used one or other of these strategies.

Table 11.1 Evidence for CAM therapies as augmentation in depression and co-morbid anxiety
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Table 11.2 Evidence for CAM therapies as augmentation in unipolar depression
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Table 11.3 Evidence for CAM therapies as augmentation in bipolar disorder
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Table 11.4 Evidence for CAM therapies as augmentation in anxiety disorders
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2 Supplements

2.1 Herbal Remedies

Herbal remedies are non-prescription, natural health products derived from plants and plant extracts, such as leaves, flowers, roots, bark and berries. They are frequently used individually or in combination to support general wellness or resolve symptoms of physical or mental stress. A literature search on the use of herbs as augmenting or combination agents found research evidence relating to St. John’s wort, lavender, and kava kava, as well as specific Chinese and Japanese herbal compounds.

Several other herbs that have been evaluated only as monotherapy in depressive and anxiety disorders, and are therefore not reviewed in this chapter. These include saffron (Crocus sativus), roseroot (Rhodiola rosea), borage (Echium amoenum), gingko biloba, passionflower (Passiflora incarnate) and valerian (Valeriana officinalis) see reviews [9, 66, 67].

2.1.1 St. John’s Wort

St. John’s wort (Hypericum perforatum) is a flowering plant whose extracts, which include hypericin and hyperforin, are candidates for its active ingredients [68]. Though St. John’s wort has shown some efficacy in depressive and anxiety conditions, its mechanism of action is not fully elucidated. It is proposed that such action may be mediated by its effect on monoaminergic systems and modulation of hypothalamic-pituitary adrenocortical (HPA) axis activity [66, 68].

A number of randomized controlled trials (RCTs) and meta-analyses have supported the efficacy of St. John’s wort as a monotherapy for mild to moderate unipolar depression, against both placebo and antidepressant comparators [e.g. 69, 70]. Surprisingly, it has not yet been evaluated as add-on to psychotropic medications, but the literature does report on two studies of St. John’s wort in combination with other herbs for MDD and co-morbid anxiety. Among these, one small cross-over placebo-controlled RCT evaluated the combination of kava kava (Piper methysticum), a leafy plant though to have similar mood modulating effects [71], with St. John’s wort. The St. John’s Wort + kava kava combination was significantly superior to placebo alone in reducing depressive symptoms in the initial phase, but there were no group differences in the second phase, after cross-over [16]. Neither treatment improved anxiety symptoms, and though no serious side effects were reported, drop out rates were high, likely due to lack of efficacy. In a second, large open trial, patients were randomized to low-dose or high-dose valerian (Valeriana officinalis), another flowering plant with putative antidepressant and anxiolytic properties [72], combined with St. John’s Wort [17]. Depressive and anxiety symptoms improved significantly and comparably in both treatment groups, though exact significance values were not reported [17]. The combination was well tolerated.

St. John’s wort has been evaluated only to a limited extent in anxiety conditions. Small placebo-controlled RCTs found no benefit to St. John’s wort monotherapy in SAD or OCD subjects [73, 74], though a small positive open trial in OCD [75] and case reports in GAD [76, 77] have suggested some benefits. No studies were found of St. John’s wort as augmentation or combination for anxiety disorders.

Thus, St. John’s wort has only preliminary evidence as add-on to valerian for the treatment of depression and co-morbid anxiety, though it can be questioned whether the lack of a placebo control influenced results. As well, despite its seeming tolerability in these studies, caution has been advised in its use in clinical practice. Adverse effects include photosensitivity and drug interactions, leading to reduced efficacy of immunoregulatory compounds, anticoagulants, anti-infective agents, and oral contraceptives, which is attributed in part to its effect on cytochrome P450 enzymes [78]. As well, serotonin syndrome when used in combination with antidepressants [79] and induction of mania and hypomania have also been reported in the literature [80].

2.1.2 Lavender

Lavender (Lavandula angustifolia) is a flowering plant from the mint family, and is popularly used for extraction of essential oils for perfumes and aromatherapy. In herbal medicine, it is used as a relaxant, appetite stimulant and an anti-spasmodic [81]. Its active ingredients include linalool and linalyl acetate and its potential neuropsychiatric action is thought to be multimodal, via its effects on gamma-aminobutyric acid (GABA) receptors, as well as glutaminergic and cholinergic systems and ion channel functioning [81].

Monotherapy trials of lavender in depressive disorders are lacking, but one augmentation study was found. A small, 3-arm, placebo-controlled RCT found significant benefit in MDD symptoms with all treatments, but impramine + lavender was superior to imipramine + placebo, with lavender + placebo showing least efficacy [19]. Reported side effects were mild and transient.

In anxiety disorders, a recent small review of the few available monotherapy trials found lavender superior to placebo (for subsyndromal anxiety), as effective as benzodiazepines (in GAD), and well tolerated see review [81]. However, there are no published studies of lavender as augmentation or combination for anxiety conditions.

Lavender shows preliminary evidence of benefit in combination with medication for MDD, which needs confirmation through larger RCTs. It has also generally been well tolerated, except for a few reported cases of allergic reaction (dermatitis) and gastrointestinal symptoms after excessive intake [81, 82].

2.1.3 Kava Kava

Kava kava (Piper methysticum) is a leafy plant whose roots are ground for herbal medicine purposes, primarily for mental and physical relaxation [83]. Its active ingredients are proposed to be several kavalactones, which are still being individually isolated [68, 83]. The kavalactones are proposed to act on GABAergic and ß-adrenergic systems, and on monoamine oxidase B (MAO-B) activity, mediating its neuropsychiatric effects [68]. In addition, effects on several monoaminergic systems have also been proposed, all of which suggests it may benefit both depressive and anxiety conditions [71].

Kava kava has not been evaluated as monotherapy or augmentation to medications in depressive disorders. However, it has been investigated in combination with other herbs in two studies of unipolar depression with co-morbid anxiety. One small placebo-controlled RCT, with a St. John’s wort + kava kava combination (previously described), had inconclusive results [16]. In a small open trial, patients randomized to calcium combined with high-dose or low-dose kava kava showed significantly greater benefit for anxiety than those on calcium alone, but all three groups showed significant and similar reduction in depression [18]. Side effects were mild and tolerable. A limitation of the study is that patients were included based only on self-reported moderate anxiety and subsyndromal depressive symptoms, and not evaluated by objective ratings.

Though placebo-controlled RCTs in anxiety disorders have had mixed results with kava kava monotherapy [66], a single open label monotherapy trial had positive results [84] and the only medication comparator RCT found it as effective as conventional anxiolytics [85]. Small meta-analyses of six monotherapy RCTs each have found it superior to placebo in reducing anxiety, though effect sizes were small [86, 87]. No studies have evaluated kava kava as add-on to pharmacotherapy in anxiety disorders, but one study has investigated its benefit in combination with non-psychotropics. In a small RCT, GAD symptoms in menopausal women improved significantly more with the combination of hormone replacement therapy (progesterone included [HRT] or excluded [ERT]), with kava kava, than with HRT + placebo or ERT + placebo [59]. Subjects did not report any side effects.

The limited literature suggests that kava kava’s proposed utility in depression has not been substantiated, but it may have some potential benefit as a combination agent for anxiety conditions. No serious side effects were reported in the above studies, however, recent case reports of liver toxicity have raised concerns about its long-term use, and have led to its being withdrawn from markets in several countries [83, 88]. Excessive intake has also been linked to skin and neurological disorders, and rare cases of drug-drug interactions, including with psychotropics, anticonvulsants, and drugs for neurological, kidney or liver function, have been reported [88, 89].

2.1.4 Herbal Compounds

Herbal compounds consist of herbs with individual health-promoting properties, which are thought to have synergistic effects when combined into a single product. Several reports have evaluated herbal compounds as adjunct in depressive disorders, but there are no such studies in anxiety conditions.

Among available publications, two large RCTs evaluated the efficacy of a well-established Chinese polyherbal compound called Free and Easy Wanderer Plus (FEWP) in bipolar disorder. Its 11 ingredients are reported to act on multiple monoaminergic and benzodiazepine receptors, as well as neurosteroid and cytokine function, accounting for its antidepressant and anxiolytic effects [90–92]. A three-arm RCT found the combination of carbamazepine (CBZ) and FEWP more effective than CBZ + placebo in improving bipolar depressive symptoms, with placebo alone being least useful [41]. The CBZ combination groups also improved mania significantly, compared to placebo. Reported side effects were mild, with CBZ + FEWP better tolerated than CBZ + placebo, suggesting that FEWP may alleviate some of the adverse effects of CBZ. A continuation phase included only the CBZ combination groups and found that further symptom improvement was comparable between groups, but that discontinuation rates were much lower with CBZ + FEWP [42]. It should be noted that FEWP has been investigated in several RCTs in depressive disorders published only in Chinese, which are therefore not reviewed in this chapter; Results from these mostly positive studies were included in a recent large systematic review of 26 studies [93] and a meta-analysis of 14 studies (which included 8 augmentation studies) [20]. While the former included small studies with methodological issues [94], publications for the meta-analysis were selected more rigorously [20]. Both reports found FEWP to be effective and tolerable as monotherapy and augmentation to medication in various depressive disorders, including major depression, dysthymia and bipolar depression [20, 93], and was also better tolerated (as monotherapy or augmentation) than conventional agents alone [20]. FEWP has no published reports as monotherapy or augmentation in anxiety disorders.

Among other reports, a small open trial augmentation of current antidepressants with a Japanese herbal compound, Jio-zai (a combination of two other well-established compounds, Rokumigan and Hachimijiogan), was found to reduce residual symptoms in MDD, but only a small percentage of patients were reported to be “much improved” [21]. Statistical significance of efficacy was not reported. Side effects were few and tolerable. The mechanism of antidepressant action of the compound, or its ingredients, is unclear. There are no reports of Jio-zai as monotherapy in depressive, nor any reports (as monotherapy or augmentation) in anxiety conditions.

While FEWP has reasonable evidence of benefit as an augmentation agent in both unipolar and bipolar depression, there is insufficient evidence to evaluate Jio-zai. Though both compounds were well tolerated, the sparse safety data available in English publications, and their limited use outside their countries of origin, would encourage caution in clinical use.

2.2 Nutraceuticals

Nutraceuticals are non-prescription, natural health products that are usually concentrated forms of naturally occurring substances, such as vitamins and minerals. They are often used individually or in combination to support good nutrition and general wellness. A literature search on the use of nutraceuticals as adjunctive agents found information relating to omega-3 fatty acids, S-adenosylmethionine (SAM-e), Dehydroepiandrosterone (DHEA), tryptophan, the B vitamins, inositol, magnesium, zinc, amino acid formulations, and proprietory vitamin-mineral formulations.

Several other nutraceuticals that have been evaluated only as monotherapy in depressive and anxiety disorders, and are therefore not reviewed in this chapter, include alpha-lactalbumin (a tryptophan-rich protein fraction), acetyl-L-carnitine (a modified amino acid and acetyl ester of quaternary ammonium compound, L-carnitine) and lysine (an amino acid and precursor of L-carnitine) see reviews [9, 66, 67].

2.2.1 Omega-3 Fatty Acids

Omega-3 fatty acids are polyunsaturated fatty acids involved in multiple biological systems, including the nervous system. Omega-3 fatty acid formulations include highly purified estyl esters of eicosapentanoic acid (EPA) or docosahexaenoic acid (DHA) or a combination of both. Their possible neuropsychiatric effect may result from modulation of neuronal communication and their impact on monoaminergic neural systems [94, 95]. A large meta-analysis of 14 studies recently noted a correlation between low omega-3 levels and depressive disorders [96], and low omega-3 levels have also been linked to anxiety conditions [97–99].

The efficacy of omega-3 fatty acids as monotherapy or augmentation in depressive disorders has been the subject of several medium-size meta-analyses that included seven to nine studies each. In both unipolar and bipolar depression, results from several meta-analyses that included both monotherapy and augmentation studies have been inconclusive, with significant heterogeneity between studies noted, as well as speculation about publication bias, with positive results more likely to be reported than negative ones [e.g. 100–102]. The meta-analyses included studies from a range of diagnostic categories, e.g. unipolar and bipolar depression, schizophrenia, as well as other psychiatric or medical conditions in which depressed mood was exhibited, which may have affected results. However, a recent meta-analysis that focused only on six augmentation studies in bipolar disorder reported clear benefit for omega-3 as add-on to antidepressants or mood stabilizers for bipolar depression, but only a trend favouring it as augmentation in mania [43]. The study populations were more homogeneous, and the likelihood of publication bias was noted to be low, though effect sizes were larger in studies with smaller samples. In all studies, omega-3 fatty acids were well tolerated, with reported side effects being mild.

The question has also been raised about which of the omega-3 fatty acids is more useful in depression. Meta-analyses suggest that EPA may be more effective than DHA or EPA + DHA, but due to confounding factors (i.e. degree of baseline depressive severity and variability of omega-3 formulation used), definitive conclusions could not be reached [103, 104].

There are no monotherapy trials of omega-3 fatty acids in anxiety disorders. Data on their use as augmentation is limited to two studies. In one small cross-over RCT, there was no reduction in OCD symptoms with either EPA or placebo augmentation of SSRIs, though EPA was well tolerated [61]. Similar non-efficacy but good tolerability of EPA (as monotherapy or augmentation to SSRIs) was seen in a small open-label case series in PTSD [64].

In conclusion, omega-3 fatty acids have moderate evidence of benefit in depressive disorders, with more robust effects seen in bipolar samples. There is no current evidence for its benefit in anxiety disorders. The mild side effects reported with omega-3 use include diarrhoea, nausea and a fishy aftertaste, but these rarely lead to discontinuation [105, 106]. While there is also evidence to support its cardioprotective benefits [107], it has been noted to increase bleeding tendencies among patients on the anticoagulant, coumadin (warfarin) and anti-platelet medications (acetylsalicylic acid, clopidogrel), with a need for monitoring [108]. Induced hypomania has been reported in a few cases, but this risk has not been noted in systematic reviews or meta-analyses of studies in bipolar depression [e.g. 43, 101, 109].

2.2.2 S-Adenosylmethionine (SAM-e)

SAM-e is a naturally occurring molecule found in the body and a derivative of the amino acid, methionine. It serves as a methyl donor in many biological processes [110]. As with several other CAM agents, its benefits has been attributed to its enhancement of monoaminergic neurotransmission [110]. However, studies that examined the association between low SAM-e levels and depression have had mixed results [111–113]. Synthetic SAM-e is available as a non-prescription oral natural health product in North America, but requires medical prescription in Europe.

While several systematic reviews and meta-analyses support the benefit of SAM-e as monotherapy in unipolar depression (as superior to placebo and comparable to TCAs) [e.g. 114–116], only two studies of adjunctive SAM-e in depressive disorders were found, and none in anxiety. In one small RCT in treatment-resistant major depression (TRD), SAM-e augmentation of SSRIs or selective norepinephrine reuptake inhibitors (SNRIs) produced significantly higher response and remission than placebo add-on [22]. Side effects were mild, and discontinuation due to adverse effects was similar between groups, but that due to lack of efficacy was higher with placebo. Similar efficacy and tolerability were noted in a small open trial of oral SAM-e augmentation to SSRIs/SNRIs in TRD [23].

No data was found for SAM-e as monotherapy or augmentation in anxiety disorders.

The limited data above offers only preliminary support for SAM-e as augmentation in TRD, but further investigation is encouraged by the evidence for its benefit as monotherapy. SAM-e is generally well tolerated with few adverse events, which include nausea, jitteriness, and loose stools [106]. Case reports suggests the risk of induction of manic episodes in vulnerable patients, and of serotonin syndrome when it is added to first-line antidepressants [117], though neither have been reported in systematic reviews or in the studies described above.

2.2.3 Dehydroepiandrosterone (DHEA)

DHEA is a natural adrenosteroid that converts to the sex hormones, testosterone and estrogen, in the body. Often used as an anti-aging supplement (though with uncertain benefits) [118], it is thought to modulate monoaminergic and glutaminergic neurotransmission, as well as provide neuroprotective and anti-oxidant benefits [119–121]. The association between DHEA levels and affective symptomatology is unclear; some studies have linked low DHEA levels to depressive symptoms [122, 123], while others have found an association with high DHEA levels [124, 125]. Curiously, both low and high DHEA levels have been linked to depressive symptoms in women [126, 127]. High levels of DHEA have also found in anxiety conditions [128, 129].

The literature on the use of DHEA in depressive disorders is very small. The few published monotherapy studies have reported benefits in MDD and dysthymia [130–132]. Only one augmentation study in depressive disorders was found. In that small RCT, DHEA (either as monotherapy or augmentation to antidepressants) significantly improved depressive symptoms in unipolar and bipolar patients, compared to placebo, and was also well tolerated [24]. Of note, the bipolar sample was limited to two patients.

No published data was found for DHEA as monotherapy or augmentation in anxiety disorders.

This pilot data suggest that further investigation of DHEA an augmenting agent in mood disorders may be fruitful. Though no serious side effects were reported in the above studies, DHEA, as a precursor of more potent sex hormones, has potential for side effects that may include acne and hirsutism, and several studies have excluded patients with prostatism or family history of breast cancer [130, 131]. Safety data also suggest monitoring for potential effects of DHEA on blood clotting, liver damage, induction of mania in vulnerable individuals, and dose-related increase in adverse effects [133, 134].

2.2.4 Tryptophan

Tryptophan is a dietary amino acid that is converted to 5-hydroxy tryptophan (5-HTP) and then into serotonin (5-HT), both centrally and peripherally. Thus, it is thus thought to enhance serotonergic neurotransmission through “precursor loading” [135]. It is a prescription drug in Canada, and recently was reintroduced in the US. Tryptophan depletion is associated with worsening of mood and cognitive functioning both in patients with a history of depression and those at risk for depression [136, 137]. In studies, tryptophan has been used in both 5-HTP and l-tryptophan formulations.

Several early studies have evaluated 5-HTP as monotherapy or augmentation to SSRIs and TCAs in unipolar and bipolar depression, with generally positive results seen in the mostly monotherapy open trials, but equivocal results in ‘blinded’ RCTs see review [138]. However, a small monotherapy meta-analysis [135] and a large review (that included six augmentation studies) [138] noted the many methodological flaws in the included studies (all published prior to 1992) and reported inconclusive efficacy of 5-HTP [135, 138]. More recently, a small placebo-controlled RCT found fluoxetine + l-tryptophan combination produced early onset of improvement in MDD, but which was not sustained to endpoint, though the combination was well tolerated [25]. A small open CAM study found l-tryptophan augmentation significantly improved depressive symptoms in patients with seasonal affective disorder who did not initially respond to light therapy, and it was also well tolerated [26]. However, due to the lack of a comparison group, it can be questioned whether longer treatment with light therapy alone might have produced a similar result.

In anxiety disorders, the data on tryptophan is very sparse. One early RCT found 5-HTP monotherapy no different from placebo and inferior to TCAs for PD [139]. There are no studies of tryptophan as add-on in anxiety conditions.

The preliminary support for tryptophan as an augmenting agent in depressive disorders needs verification through further RCTs. It has no evidence of benefit in anxiety disorders at this time. Side effects usually reported with tryptophan include drowsiness, dry mouth, nausea, and other gastrointestinal symptoms, but reports of serotonin syndrome are relatively rare in RCTs [135, 138]. In 1989, tryptophan ingestion was associated with an outbreak of Eosinophilia-Myalgia Syndrome that resulted in significant mortality, but this was attributed to a contaminated batch from a single manufacturer, and no such reports have emerged since then [135, 138].

2.2.5 The B Vitamins

The water-soluble B vitamins are found in foods and are vital to the growth, division and metabolism of cells, as well as for immune and nervous system functioning. They consist of thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid or folate (B9) and assorted cobalamins (B12). Vitamin B9 (folate) is implicated in monoaminergic synthesis [140], and is the most studied as a CAM therapy, but Vitamins B6 and B12 have also been investigated. Folate and Vitamin B12 are both necessary for production of homocysteine which is converted to methionine, a precursor to S-adenosyl methionine, which is a methyl donor involved in neurotransmitter function [140, 141]. Several studies have noted low levels of folate (in particular) and Vitamin B12 in depressed patients [e.g. 142, 143], though others have failed to confirm this association [e.g. 144, 145]. Similarly, studies evaluating the association between low Vitamin B6 levels and depression have had both positive [e.g. 146, 147] and negative [e.g. 144, 145] results. No associations have been noted between these B vitamins and anxiety disorders, thus far. Other research has focused on choline, a nutrient in the B vitamin family that is a precursor for the neurotransmitter, acetylcholine, and which also supports phosphate production in the brain [44]. Low levels of acetylcholine and of phosphates have been linked to mania [44, 148], as have low levels of choline [45, 149], but the data is not robust. Elevated choline levels have been found in depression [150, 151], while low levels have been correlated with anxiety [152, 153].

Folate: Several investigations have evaluated the efficacy of folate in depressive disorders. In an early placebo-controlled RCT, folic acid augmentation significantly improved depressive symptoms in unipolar depressed patients, but not in bipolar or schizophrenia patients [27]. However, the patients were only marginally depressed at the start of the study, which was a limitation. Side effects were comparable and tolerable across groups. Another early placebo-controlled RCT found methylfolate augmentation of tricyclic antidepressants (TCAs) or monoamine oxidase inhibitors (MAOIs) significantly superior to placebo in improving depressive symptoms in MDD and schizophrenia, though tolerability data was not reported and sample size was small [28]. Subsequently, an adequately-sized RCT found fluoxetine + folic acid combination superior to fluoxetine + placebo in MDD, but only among female patients, and it was also better tolerated than the placebo combination [29]. This was followed by a small open trial that found folinic acid augmentation of SSRIs to be significantly effective in improving TRD and well tolerated, but only a small percentage of patients achieved response or remission levels [30]. The findings of these four studies were included in recent small systematic reviews of folate in unipolar depression, which found it effective as both monotherapy and augmentation [154, 155], and well tolerated [154]. More recently, folic acid augmentation of fluoxetine was found significantly superior to placebo augmentation in a small RCT in MDD; tolerability data is unknown [31]. Paradoxically, a small open randomized trial found escitalopram monotherapy significantly superior to escitalopram + folic acid combination in MDD, but with tolerability data not reported [32]. A recent large retrospective analysis of 242 cases, which compared the efficacy of l-methylfolate co-initiated with antidepressant therapy to antidepressant therapy alone in MDD, found that the folate combination was associated with significantly better treatment response, faster onset of improvement and less discontinuation due to side effects than antidepressants alone [33]. In the only study in bipolar disorder, an adequate-sized RCT found that both valproate + folic acid and valproate +placebo combinations significantly improved manic symptoms and were well tolerated; the folic acid combination showed statistical superiority to placebo only at end of the brief treatment period [46]. There is no data on folate as monotherapy or augmentation in anxiety disorders.

Vitamin B12: Literature on the use of Vitamin B12 is very sparse. A single early monotherapy RCT found no difference between Vitamin B12 and placebo in seasonal affective disorder [156]. No augmentation or combination studies were found with Vitamin B12 in other mood and anxiety conditions.

Vitamin B6: A recent small systematic review of the efficacy of Vitamin B6 as monotherapy or augmentation in unipolar depression found no benefit for its use, and noted limitations of small sample size and heterogeneity of patient populations [157]. The only published augmentation study, a small placebo-controlled RCT which used a B complex vitamin (comprised of Vitamins B1, B2 and B6), as add-on to TCAs, was included in the review, and also had negative results [158]. There are no reports of Vitamin B6 as monotherapy or augmentation in anxiety conditions.

Choline: There are no studies of choline monotherapy in depressive disorders. Choline augmentation has been evaluated in bipolar disorder in two studies, with mixed results. In a small open label case series, choline bitartrate augmentation of lithium significantly improved depressive and manic symptoms in most patients and was well tolerated, but important study data was not published, including duration of treatment and statistical significance values [45]. In a small RCT, choline bitartrate or placebo augmentation of lithium had no effect on bipolar depression or mania; no tolerability data was reported [44]. No investigations of choline as monotherapy or augmentation in anxiety conditions are currently available.

Thus, evidence is lacking for Vitamin B6, Vitamin B12 or choline as augmentation in depressive disorders. However, there is reasonable evidence for folate as augmentation or combination to medication for MDD. Folate was well tolerated in all reported studies, and there are no known drug interactions or contradictions to the use of methylfolate [140]. However, there is evidence that high folate doses (>800 mcg) may lead to increased levels of unmetabolized serum folic acid, which can lower levels of natural killers cells and brain l-methylfolate and deplete monoamines, and may worsen depression [140, 154]. Folic acid, in high doses (e.g. 15 μg), has been associated with increased depression in some studies, and sleep difficulties, irritability, hyperactivity and discomfort have also been reported in healthy volunteers [140, 159].

2.2.6 Vitamin D

Vitamin D is a fat-soluble secosteroid that is found in foods and is also naturally produced by the body during adequate sun exposure. Essential to bone health, it acts through prevention of bone demineralization and promotion of calcium absorption, and is also thought to influence cellular and kidney function [160, 161]. It has been postulated that Vitamin D may affect mood through its modulation of serotonin synthesis and glucocorticoid activity, and may also be neuroprotective [162, 163]. While several epidemiological studies have reported an association between low serum vitamin D levels and depression e.g. [164–166], others have not confirmed such links [167, 168]. It has also been suggested that any relationship may be seasonally influenced [169, 170] and may have a female gender skew [171].

Reviews of the limited research on Vitamin D monotherapy in depression have noted only modest benefit in seasonal affective disorder and methodological weaknesses in many of the studies found, limiting the generalizability of results [161, 167]. Thus, the role of Vitamin D in depressive disorders (as a cause, consequence or associate) also remains unelucidated [157, 167]. No published studies have evaluated Vitamin D as an add-on in depressive disorders, or as monotherapy or augmentation in anxiety conditions.

Evidence is currently lacking to recommend Vitamin D as an agent for depressive or anxiety disorders. However, it continues to be recommended as a dietary supplement for general health benefits at a dosage of up to 2,000 IU per day [172]. Toxicity has been reported at dosages over 20,000 IU per day, and has included gastrointestinal symptoms, low appetite and hypercalcemia [172, 173].

2.2.7 Inositol

Inositol is a carboxylic polyol, an isomer of glucose that is integral to the production of cellular secondary messengers, such as inositol triphosphate, that mediates neurotransmitter receptor activity, and in turn, intracellular processes [34]. The association between low inositol levels and depression is equivocal, with some studies noting a correlation [174–176], but others not [177]. Low levels of inositol have also been linked to anxiety in animal models [178, 179].

There is a small body of literature on the use of inositol in depressive disorders. No group differences were noted in two small placebo-controlled RCTs of inositol add-on to SSRIs in MDD [35, 36]. It had comparable tolerability to placebo in the first study [35], but in the other, drop out due to side effects (including one case of serotonin syndrome) was greater with inositol than with placebo [36]. In bipolar disorder, a small RCT failed to find group differences between inositol or placebo augmentation of mood stabilizers in bipolar depression, though it was well tolerated [47]. A small meta-analysis of four studies in depressive disorders, which included these three studies (and one placebo-controlled monotherapy RCT), also found no evidence of benefit for inositol as monotherapy or augmentation in unipolar or bipolar depression [34]. More recently, a two-phase study in bipolar depression failed to note any benefit to inositol augmentation of mood stabilizers in its placebo-controlled RCT phase (though a trend favoured inositol) [48]. The subsequent open label continuation phase supported inositol augmentation, though significance values were not reported. Another small open trial, an arm of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, found randomized augmentation with lamotrigine, inositol or risperidone to be comparable in efficacy and tolerability in bipolar depression [49].

In anxiety disorders, a small review found modest benefits with inositol monotherapy in PD and OCD, with inositol showing superiority to placebo, comparable efficacy to SSRIs, and good tolerability [67]. However, these benefits were not replicated in the only two augmentation studies with inositol, both in OCD. No significant benefit was noted to inositol augmentation of SSRIs/TCAs in either a cross-over placebo-controlled RCT [62], or an open trial [63]. Side effect data, available for only one of the studies, found inositol to be well tolerated [63].

Thus, overall, there is insufficient evidence to recommend inositol as an augmenting agent in either depressive or anxiety disorders. It appears to be well tolerated, but induction of mania or hypomania, and hospitalization due to worsening of psychiatric symptoms, have been reported in case reports, as well as in some patients in clinical trials [35, 47, 48, 180].

2.2.8 Magnesium

Magnesium is an essential mineral that is integral to cellular and neuronal functioning in the brain [181]. It modulates both N-methyl-D-aspartic acid (NMDA) and GABA neurotransmission, suggesting a possible route of antidepressant action, but is also thought to modulate HPA axis activity, and thus stress and anxiety pathways [182–184]. Magnesium deficiency is associated with increased vulnerability to stress reactivity, depression and anxiety in animal models [181, 185], and to post-partum depression in humans [186].

Data on magnesium supplementation in mood and anxiety disorders is limited. A recent small review of mostly early studies noted that monotherapy with magnesium supplements appeared to benefit depression, mania and anxiety, but heterogeneity of study populations, variation in formulations used and lack of RCT data limit the value of the findings [187]. Only two augmentation studies were found in depressive disorders, both in bipolar patients. In the first, a small open case series, intravenous (IV) magnesium sulfate augmentation of existing mood stabilizers or benzodiazepines improved refractory mania, though no statistical significance values were reported [50]. Significant side effects of brachycardia (frequent) and burning sensation in the veins (rare) were resolved with reduction in IV dosage. In the other, a small RCT, magnesium oxide augmentation of verapamil was found significantly superior to placebo augmentation for mania, but tolerability data was not reported [51].

Any published evidence for magnesium monotherapy for anxiety symptoms is challenged by methodological flaws, particularly the lack of distinct syndromal anxiety patient samples [187]. In the only add-on study available, a large RCT in GAD combined hawthorn (Crataegus oxyacantha; a fruit-bearing shrub), and California poppy (Eschscholtzia californica; a flowering plant), both thought to have anxiolytic properties [188, 189], with elemental magnesium and found the combination to be significantly superior to placebo in improving GAD symptoms [60]. Side effects were mild with both treatments.

This preliminary data is promising, but there is currently insufficient evidence to recommend magnesium augmentation for depressive or anxiety disorders. Though magnesium is generally well tolerated in over-the-counter formulations, the absence of long-term safety data is also a cautionary note, in particular as excess intake of magnesium has been linked to gastrointestinal upset and cardiac arrhythmia [186, 190].

2.2.9 Zinc

Zinc is an essential mineral that is involved in ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) metabolism, signal transduction, and gene expression, and is a component in enzymes, amino acids and proteins [191]. Its exact role in the pathophysiology of mood and anxiety disorders remains unclear. One hypothesis is that deficiency of zinc (found in highest concentrations in the hippocampus and amygdala) [192], leads to reduced hippocampal neurogenesis [193], and in turn to the decreased hippocampal volumes reported with depression and anxiety [194, 195]. Zinc is also suggested to modulate NMDA-receptor activity, pharmacological antagonists of which have been shown to benefit both depression and anxiety [196, 197]. It is also posited to support serotonergic signaling [198, 199], and to improve neuroplasticity by increasing BDNF gene expression [200, 201] and glutathione levels [202], an effect similar to that of antidepressants [203, 204]. Thus, it may have several modes of antidepressant and anxiolytic action. Zinc deficiency is associated with anxiety in animal models [205, 206], while human studies have noted a correlation between zinc deficiency and depression [e.g. 207, 208].

There are no monotherapy studies of zinc as intervention in depressive disorders. A recent small meta-analysis of four studies (two monotherapy studies in healthy subjects and two augmentation RCTs in depressed subjects) found zinc to be superior to placebo as augmentation to SSRIs/TCAs in unipolar depression [37]. However, methodological flaws restrict generalizability of the results. Both RCTs had small MDD samples [38, 39]. Furthermore, in one RCT, the zinc combination was superior to placebo add-on only in the antidepressant-resistant subgroup and only at midpoint, with only a trend to superiority in this subgroup at endpoint [39]. Zinc was well tolerated in both studies.

There are no published studies of zinc as monotherapy or augmentation in anxiety disorders.

This limited but promising data suggest that more and larger placebo-controlled RCTs would be useful to help determine the utility of zinc for depression. In the above studies, zinc supplementation was well tolerated and no drug-drug interactions were reported. However, there are reports of excess zinc consumption being associated with ataxia, lethargy, iron and copper deficiency, and cerebral ischemia [209–211].

2.2.10 Other Dietary Supplements

Additional studies on adjunctive use of other dietary supplements in mood and anxiety disorders have reported on the benefits of several amino acid formulations or proprietary vitamin-mineral formulations.

While several amino acids are produced by the body, others are only found in foods. Though mostly known for their key role in protein synthesis, amino acids are also important in many physiological processes, including synthesis of neurotransmitters, by which effect they may influence affective state [212, 213]. Disturbances in amino acid levels have been reported with depression, and improvement in amino acid levels has been seen with antidepressant treatment response [214, 215]. Among individual amino acids, a few small and mostly early RCTs found acetyl-L-carnitine as monotherapy to be superior to placebo and comparable to atypical antipsychotics in unipolar depression, and to be well tolerated [216–219]. However, there is no published data to support its benefit as augmentation. On the other hand, while amino acid formulations have not been evaluated as monotherapy in depressive disorders, there are two augmentation studies in the literature. In a small RCT with an amino acid mixture (comprised of ten amino acids, 11 vitamins and three minerals), response in severe MDD was significantly greater with mirtazapine + amino acid mixture than mirtazapine + placebo, though remission rates and tolerability were similar [40]. Another small RCT found augmentation with a branched-chain amino acid drink (consisting of three amino acids) produced faster onset of improvement in bipolar mania than placebo; group differences disappeared by end of treatment, but re-emerged in favour of amino acids at 1-week follow-up [52]. The amino acid drink was well tolerated. There are no studies of amino acids as monotherapy or augmentation in anxiety disorders.

N-acetylcysteine (NAC) is acetylated derivative of the amino acid, cysteine, which is the precursor of glutathione, the main antioxidant in the brain [220]. Impaired glutathione metabolism is linked to increased oxidative stress, which, in turn, is thought to underl the pathophysiology of several psychiatric disorders, including depression [220, 221]. NAC has no monotherapy data in depressive disorders, but there are two maintenance augmentation studies in bipolar disorder. A small placebo-controlled maintenance RCT found NAC augmentation to existing psychotropics (antidepressants, mood stabilizers, antipsychotics, etc.) produced significant improvement in bipolar depressive symptoms, quality of life and functioning; a trend to improvement in manic symptoms may have been moderated by the low mania scores at study onset [53]. There were no group differences in time to mood episode, and NAC was generally well tolerated. Similar benefits with NAC augmentation of existing psychotropics were also noted in the results from the large open trial stage of a two-phase maintenance RCT by the same research group, though side effect data were not reported [54]. Results of the subsequent double-blind phase are pending. No studies were found with NAC as monotherapy in anxiety disorders, but a single case report suggests its benefit as augmentation to SSRIs [222].

A proprietary nutritional supplement made up of 36 chelated trace vitamins and minerals, called E. M. Power Plus (EMP+), has also been investigated in bipolar disorder. It is thought to alleviate bipolar-like symptoms by correcting nutritional deficiencies that may contribute to metabolic dysfunction [55]. Three case series with adult patients have noted significant improvement in bipolar depressive and manic symptoms with EMP + (as monotherapy or augmentation), leading to significant reduction in psychotropic medication use [55–57]. Only one of the case series reported significance values, but it had a small sample and almost all patients were male, limiting generalizability [55]. In general, EMP + was well tolerated in these studies, with few side effects. Hypomanic switch was reported in two cases, as well as symptom recurrence in some subjects post-study, needing resumption of psychotropics [57]. A recent large database analysis of open label EMP + monotherapy or augmentation in child and adolescent bipolar patients noted similar efficacy and tolerability with EMP+, but lack of RCTs hinder definitive conclusions [58]. A systematic review of the safety and tolerability of EMP + found that it was well tolerated in both adult and youth populations, with mild and transitory GI symptoms and headache most reported, no abnormal lab results or toxicity, and fewer adverse events and lower weight gain than with psychotropics [223]. There is no data on the use of EMP + as monotherapy or augmentation in anxiety conditions.

There is only preliminary evidence for the benefit of amino acid compounds, and due to the variability in formulation between studies, data is insufficient to make recommendations. The pilot data on NAC augmentation for bipolar depression appears promising and if the pending data from the double-blind phase of the latest study [54] is positive, it may support the use of NAC in this disorder. While the preliminary efficacy data with EMP + in bipolar disorder also appears to warrant further placebo-controlled investigations, it must be noted that the only such trial registered on clinicaltrials.gov was discontinued due to recruitment difficulties, large expectancy effects and uninformative results [224]. Side effects reported with the above supplements appear to be mild and tolerable, for most part. However, due to the general paucity of evidence, their utility in clinical practice remains undefined.

3 Conclusions and Future Directions

Although clinical trials of herbal and dietary supplements as augmentation or combination in mood and anxiety disorders are being increasingly reported, they are still significantly fewer than those with conventional pharmacological agents. As this review has also shown, research on the supplementary use of these compounds is much more common for depressive disorders than for anxiety conditions.

It is of note that despite the general dearth of efficacy and tolerability data with the CAM agents reviewed in this chapter, there is relatively good information on the basic physiological mechanism of action of many of them. Enhancement of monoaminergic and glutaminergic neurotransmission, impact on HPA axis functioning, and enhanced neurogenesis, have been reported to result from the use of several of these agents, as with conventional antidepressants. Large head-to-head effectiveness trials against first-line antidepressants may prove to be valuable.

Based on the evidence from available studies, the herbal and dietary supplements that appear to hold most promise as adjunctive agents to pharmacotherapy include the herbal supplement, FEWP (in unipolar depression, bipolar depression or mania), and the nutraceuticals, omega-3 fatty acids (in bipolar depression) and folate (in MDD). There is also preliminary evidence of benefit for combination with some other herbal remedies, such as lavandula (in MDD), and dietary supplements, such as SAM-e (in TRD), DHEA (in MDD), magnesium (in mania), zinc (in MDD), amino acid formulations (in unipolar depression and mania), NAC (as maintenance in bipolar depression), and EMP + (in bipolar disorder). Among the other supplements reviewed, St. John’s wort (for depression and co-morbid anxiety), kava (for anxiety symptoms), and tryptophan (for seasonal affective disorder) only have data in combination with non-pharmacological agents, thus far. Currently, there is insufficient evidence to support other herbal and nutraceutical agents (i.e. Jio-zai, inositol and Vitamin D) as augmentation for depressive and anxiety disorders.

While these agents were frequently effective and usually well tolerated in published studies, limited numbers of good quality RCTs and/or limited familiarity of use in clinical practice has meant that most guidelines would recommend their use usually as augmentation, and often later in the treatment algorithm. In particular, there is sparse information on their potential interaction with conventional psychiatric drugs, and as such, longer-term efficacy and safety data may help to increase support for wider clinical application.