DEPRESSION AND ANXIETY 31:379–390 (2014)

Review REVIEW OF NUTRITIONAL SUPPLEMENTS FOR THE TREATMENT OF BIPOLAR DEPRESSION Jeffrey J. Rakofsky, M.D.1 ∗ and Boadie W. Dunlop, M.D.2

Many patients view psychotropics with skepticism and fear and view nutritional supplements as more consistent with their values and beliefs. The purpose of this review was to critically evaluate the evidence base for nutritional supplements in the treatment of bipolar depression (BD). A literature search for all randomized, controlled clinical trials using nutritional supplements in the treatment of BD was conducted via PubMed and Ovid MEDLINE computerized database. The studies were organized into essential nutrients/minerals, nonessential nutrients, and combinations of nutritional products. Among essential nutrients/minerals, omega-3-fatty acids (O3FAs) have the strongest evidence of efficacy for bipolar depression, although some studies failed to find positive effects from O3FAs. Weak evidence supports efficacy of vitamin C whereas no data support the usefulness of folic acid and choline. Among nonessential nutrients, cytidine is the least supported treatment. Studies of N-acetylcysteine have not resolved its efficacy in treating acute depressive episodes relative to placebo. However, one study demonstrates its potential to improve depressive symptoms over time and the other, though nonsignificant, suggests it has a prophylactic effect. Studies of inositol have been mostly negative, except for 1 study. Those that were negative were underpowered but demonstrated numerically positive effects for inositol. There is no evidence that citicholine is efficacious for uncomplicated BD depression, though it may have value for comorbid substance abuse among BD patients. Finally, combination O3FA-cytidine lacks evidence of efficacy. The findings of this review do not support the routine use of nutritional supplements in the treatment or prophylaxis of BD depression. Studies with more rigorous designs are required before definitive conclusions can be made. Despite the inadequacy of the existing data, clinicians should remain open to the value of nutritional supplements: after all, lithium is a mineral too. Depression and Anxiety 31:379–390, 2014.  C 2013 Wiley Periodicals, Inc.

Key words: bipolar disorder; depression; pharmacotherapy; clinical trials; treatment

1 Mood

and Anxiety Disorders Program/Bipolar Disorders Clinic, Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia 2 Mood and Anxiety Disorders Program, Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia Neither Drs. Rakofsky nor Dunlop received any direct support for developing this manuscript. Over the past three years, Dr. Rakofsky has received research support from Takeda, AstraZeneca and Novartis. Dr. Dunlop has received research support from

 C 2013 Wiley Periodicals, Inc.

AstraZeneca, Bistol-Myers Squibb, Evotec, Forest, Glaxo-SmithKline, and Pfizer. ∗ Correspondence

to: Jeffrey J. Rakofsky, M.D., Mood and Anxiety Disorders Program/Bipolar Disorders Clinic, Department of Psychiatry and Behavioral Sciences, Emory University, 1256 Briarcliff Rd, 3rd Floor North, Atlanta, GA 30306. E-mail: [email protected] Received for publication 12 September 2013; Revised 26 October 2013; Accepted 2 November 2013 DOI 10.1002/da.22220 Published online 18 December 2013 in Wiley Online Library (wileyonlinelibrary.com).

Rakofsky and Dunlop

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M

INTRODUCTION

any patients with bipolar disorder (BD) struggle to be free from symptoms of depression. Over a 20-year period of naturalistic treatment, BD I and II patients spent 31.9 and 50.3% of the weeks, respectively, with depressive or subsyndromal depressive symptoms.[1, 2] These symptoms may contribute to the functional impairments in work performance and social relationships that are common among BD patients.[3, 4] Data from the Stanley Foundation Network indicate that 45% of depressed BD patients treated over the course of a year or more failed to improve or worsened clinically.[5] In that same study, partial or sustained improvers (≥6 months of improvement), required a mean of three medications, while 31.8% required 4 and 13.8% required five medications. Currently, only two treatments carry a Food and Drug Administration indication for the acute treatment of BD depression. They are quetiapine, for which there are five randomized, placebo-controlled trials that support its efficacy[6–10] and olanzapine-fluoxetine combination, for which there is only 1 published study.[11] Although psychiatrists may prescribe mood stabilizers, antidepressants, and second-generation antipsychotics off-label for BD depression, the data supporting their efficacy are limited by small sample sizes, study design issues, and/or inconsistent findings. Thus, there is a clear need for additional efficacious and tolerable treatments for BD depression. The poor outcome for many of those with bipolar depression may in part be due to the treatments themselves. Adverse effects, such as weight gain and sedation are common side effects and are often cited as the primary reason for poor adherence to treatment.[12] Many patients view psychotropics with skepticism,[13] and are likely to use natural products, as these are more consistent with their values and beliefs toward life and health.[14] Nutritional supplements include preparations of vitamins, minerals, amino acids, and other products that fulfill or exceed daily requirements for life. They can be categorized broadly into essential nutrients (must be obtained from the diet), and nonessential (can be formed by the body endogenously). Although they are not categorized as medications, many supplements have antiinflammatory, anti-oxidant, and/or intracellular signal transduction effects that have similarities with the mood stabilizers, such as lithium, valproate, and lamotrigine (Table 1). These similarities suggest that supplements may possess therapeutic potential for bipolar depression. For some patients, supplements may replete missing nutrients and restore normal physiologic activity, or, in excess, may drive specific intracellular reactions, leading to symptom reduction. There may also be an additive or synergistic effect when supplements are combined with mood stabilizers, reducing the need for additional psychotropics. Some nutritional supplements have demonstrated efficacy in randomized controlled trials for major depressive disorder.[15, 16] Depression and Anxiety

Given the need for better treatments of BD depression, we aimed to examine the evidence base for nutritional supplements through a systematic literature review. Although three qualitative reviews,[17–19] a Cochrane Database review[20] and a meta-analysis[21] have previously explored the use of nutritional supplements for bipolar disorder, they differ from this review in their scope or in the standards of evidence used for inclusion. The current review aims to provide an up-todate, comprehensive perspective on all nutritional supplements evaluated in randomized controlled trials for efficacy in BD depression.

METHODS A literature search for all randomized clinical trials of nutritional supplements and BD was conducted via PubMed and Ovid MEDLINE computerized database on June 8th , 2013. The search terms used included: “bipolar,” AND “dietary supplements” OR “nutraceuticals” OR “nutritional supplements” OR “vitamins” OR “minerals.” No limits in publication dates were applied. This search produced 394 publications. Potentially eligible studies were identified by one of the authors (JJR) based on titles and abstracts. These articles were assessed for final inclusion based on the full text. Additionally, the reference lists of all selected articles were searched for other potentially relevant studies. Final selection of studies included in this review was based on the following criteria: (1) subject sample included adult BD (I, II, or NOS) depressed or euthymic patients, (2) were randomized controlled trials, (3) reported changes in depressive symptoms or depressive episode recurrences, and (4) were written in English. Studies that enrolled both non-BD and BD subjects were included only if they reported the results for the BD subjects separately. The studies were organized into essential nutrients/minerals, nonessential nutrients, and combinations of nutritional products.

RESULTS ESSENTIAL NUTRIENTS/MINERALS

Table 2 presents the summary data of randomized, controlled trials of essential nutrients and minerals. Omega 3 Fatty Acids (O3FA). O3FA’s are polyunsaturated fatty acids that have anti-inflammatory properties and inhibit cell-signaling pathways associated with phosphatidylinositol and arachidonic acid.[22, 23] These compounds have received the greatest level of empirical testing among the nutritional supplements. However, randomized clinical trials with O3FAs face two unique challenges not present in studies of other nutritional supplements: (1) there are 2 types of O3FAs, eicosopentaenoic acid (EPA), and docosahexanoic acid (DHA) that have been used in various doses and ratios in adult bipolar clinical trials. This variable complicates the selection of the specific components to be evaluated; and (2) OF3As often have a “fishy” taste that in at least 1 study[24] contributed to unblinding of the participants as this taste was absent from the placebo tablets. Two positive and two negative randomized, double blind, placebo-controlled studies met the search criteria. Stoll et al.[24] reported antidepressive efficacy of O3FA

Review: Bipolar Depression and Nutritional Supplements

381

TABLE 1. Biological effects of nutritional supplements of potential therapeutic use for bipolar depression Supplement

Daily dose range

Omega 3 fatty acids

1–9.9 g

Folic acid Vitamin C

200 μg 3–4 g

Choline

50 mg/kg

Cytidine

2g

N-acetylcysteine Inositol Citicholine

2g 25 g 2g

Biological effects Inhibition of cell signaling pathways; anti-inflammatory; phosphoinositide-PKC antagonism; monoaminergic reuptake inhibition Neurotransmitter synthesis; DNA repair/methylation/synthesis Modulates intracellular sodium levels; anti-inflammatory; anti-oxidant; increases neurotransmitter synthesis Methyl group donor; acetylcholine synthesis; phosphatidylcholine and sphingomyelin synthesis; synthesis of secondary messengers Modulates glutamate activity; increases cerebral high energy phosphate levels; increases neurotransmitter levels; improves mitochondrial function; membrane stabilization; phospholipid metabolism Anti-oxidant; anti-inflammatory; enhances neurogenesis; modulates glutamate A precursor in the phosphatidyl-inositol secondary messenger system Increases neurotransmitter levels; increases incorporation of phospholipids into membranes; enhances synthesis of structural phospholipids

[6.5g EPA/3.4 g DHA] over placebo in 30 BD patients participating in a 4-month trial, which was stopped early after an interim analysis showed benefit. There were no statistically significant differences in adverse event frequency between the groups. A three-arm trial (ethylEPA 1 g/day, 2 g/d or placebo for 12 weeks) of 75 BD I or II patients by Frangou et al.[25] found that when the two ethyl-EPA arms were combined for analysis, ethylEPA proved superior to placebo (mean endpoint HAMD 3.3 ±1.4 points lower than placebo, P = .03) In this trial, there was an imbalance of prescription psychotropic use between the groups: at baseline, 51% of patients in both ethyl-EPA groups were taking lithium and 49% were taking antidepressants compared to 34.6 and 26.9%, respectively, for patients in the placebo group. Though loose stools and gastrointestinal discomfort were reported most commonly, there were no statistically significant differences between the groups. The negative trials of O3FA included the largest study to date, performed by Keck et al.[26] This trial randomized 57 depressed and 59 rapid cycling BD I, II, or NOS patients to receive adjunctive EPA 6 g daily or placebo for 4 months. For both the depressed and the rapid cycling groups, there was no significant difference between the groups in mean change on the Inventory of Depressive Symptoms-Clinician-rated scale (IDS-CR). Gastrointestinal symptoms were reported more often in the EPA group than the placebo group, however, these differences were not statistically significant. A small augmentation randomized controlled trial comparing ethyl EPA 2 g/d versus placebo in 14 female BD I patients who had a HAMD ≥ 10 after 12 weeks of lithium monotherapy found no significant changes between or within groups. Adverse events were not reported.[27] Folic Acid. Folic acid is a vitamin that is essential for DNA repair, methylation, and synthesis and also facilitates neurotransmitter production.[28–30] Coppen et al.[31] assessed change in depressive symptoms over one year among euthymic mood disorder (17 BD, 53 unipolar) patients on lithium who were randomized to either 200 μg of adjunctive folic acid or placebo. There

were no significant differences at endpoint within or between groups on either the beck depression inventory (BDI) or the affective morbidity index (AMI) for the BD patients. Similarly, there were no statistically significant differences in adverse event scores between the two groups. Vitamin C. Vitamin C, also known as ascorbic acid, provides anti-inflammatory and antioxidant protection, and increases neurotransmitter synthesis.[32, 33] It also modulates intracellular erythrocyte sodium levels, which are abnormal during states of mania and depression.[34] A two-day, cross-over, double-blind, placebo-controlled study of 24 BD inpatients, 12 of whom were depressed, suggested efficacy of 3 g of vitamin C over placebo for depressive symptoms assessed by the HAMD.[34] Patients were rated hourly on a global illness scale and twice on the HAMD. For the depressed patients, the global illness scale ratings on the vitamin C day were significantly lower than those on the placebo day at 3, 4, 5, and 6 hr after dosing. The authors did not report adverse events, nor did they provide a rationale for expecting rapid effects from a single large dose of vitamin C treatment. In a 28-day, randomized, double-blind, active-control study, the combination of 4 g of vitamin C/4 g of ethylene diamine tetra acetic acid (EDTA) was found to have similar efficacy as amitriptyline 150 mg/d in 61 female inpatients with BD, 32 of whom were depressed.[35] Both groups showed improvements over time on the BDI and HAMD, with no statistically significant differences between the groups at endpoint. The absence of a placebo control prevents definitive interpretations of the efficacy of vitamin C. There were no differences in the number of adverse events reported between the two treatment groups. Choline. Choline is part of the B-complex vitamins. It is a major methyl-donor, is a core constituent of the neurotransmitter acetylcholine, and is needed for structural integrity and intracellular signaling within cell membranes.[36] In a small study, Lyoo et al.[37] studied eight lithium-treated (with stable dose for the past 2 weeks), rapid-cycling, BD I and II patients randomized Depression and Anxiety

Depression and Anxiety

Study sample

Yes, Lithium NR regarding other psychotropics

1.6 ± 0.9 (BDI)

Yes, lithium only

Yes

1.6 ± 0.6

11.8 ± 2.2 (HAMD)

11.7 ± 3.4

NR

Type I and II, rapid cycling, Choline 50 mg/kg/d (N = 4) at least 1 episode per PBO (N = 4) month × 6 mos

Adjunctive psychotropic treatments allowed

16.0 ± 4.2 (HAMD)

23.5 ± 9.3

Yes

3 mos

28 days

NA

No

1 day of each treatment (CO)

1 yr

3 mos

4 mos

3 mos

4 mos

Duration

Yes

Yes

Yes

Yes

No

Yes

Adjunctive psychotropic treatments held constant

Change on HAMD: difference between groups, P = NS

Change on BDI and HAMD: difference between groups, P = NS

HAMD ratings at 4 hours: Vit C day < PBO day, P = 0.025

Folic acid: 2.6 ± 1.1 PBO: 1.3 ± 0.6, P = NS

End point BDI:

Mean difference in IDS-C -.038 ± 1.7 lower with OF3A than PBO P = NS End point HAMD: O3FA: 10 ± 4.3 PBO: 12 ± 4.1 Change within and between groups, P = NS

End point HAMD: 3.3 ± 1.4 lower for combined EPA group than PBO, P = .03

End point HAMD: O3FA: 4.9 ± 5.3 PBO: 15.7 ± 9.1, P = .002

Depression outcomes:

BDI, beck depression inventory; CO, cross-over; DHA, docosoahexanoic acid; EDTA, ethylene diamine tetra acetic acid; EPA, eicosopentaenoic acid; HAMD, Hamilton depression scale; NA, not applicable; NOS, not otherwise specified; NR, not reported; NS, not significant; PBO, Placebo.

Choline Lyoo (2003)

Kay (1984)

Type NR, depressed

Vitamin C Naylor (1981)

Folic acid 200 μg/d (N = 11) PBO (N = 6)

Yes

14.7 ± 4.3 Yes 14.8 ± 5.6 15.4 ± 5 (HAMD)

12.6 ± 9.1 (HAMD)

9.5 ± 5.7

Baseline severity

Vitamin C 3 g/d NR Yes (N = 12) PBO (N = 12) 16.0 ± 6.6 No Type NR, depressed, female Vitamin C 4 g/d EDTA 4 g/d (N = 18) Amitriptyline 50 mg/d 19.3 ± 5.8 (HAMD) (N = 14)

Type NR, euthymic

Folic acid: Coppen (1986)

Frangou (2007)

Keck (2006)

EPA 6.5 g/d DHA 3.4 g/d (N = 14) PBO-olive oil ethyl esters (N = 16) EPA 1g/d (N = 24) EPA 2 g/d (N = 23) PBO-liquid paraffin (N = 26) Type I, II, NOS, Depressed EPA 6 g/d (N = 59) or rapid cycling PBO-liquid paraffin (N = 57) Type I, depressed, HAMD EPA 2 g/d (N = 7) ≥ 10, Lithium monotherapy ≥ 12 wks PBO-liquid paraffin (N = 7)

Omega 3 fatty acids (O3FA’s) Stoll (1999) Type I or II, Index episode NR, Had at least 1 (hypo)manic episode in the last year. Frangou (2006) Type I or II, depressed, HAMD ≥ 10

Author (year)

Treatment arms/ (N bipolar)

TABLE 2. Randomized controlled trials of essential nutrients and minerals for bipolar depression

382 Rakofsky and Dunlop

Review: Bipolar Depression and Nutritional Supplements

to receive either a minimum of 50 mg/kg/day of choline or placebo for 12 weeks. At end-point, there were no within or between group differences on the HAM-D, YMRS, or CGI-S. Adverse events were not reported. Summary. Among essential nutrients/minerals, O3FAs have the strongest evidence of efficacy for bipolar depression, though there are also studies that failed to demonstrate positive outcomes. Weak evidence supports efficacy of vitamin C whereas no data support the usefulness of folic acid and choline. NONESSENTIAL NUTRIENTS

Table 3 presents the summary data of randomized, controlled trials of nonessential nutrients. Cytidine. Cytidine is a nucleoside molecule. It modulates glutamate activity, increases neurotransmitter synthesis, and plays a role in membrane stability.[38–40] Yoon et al.[41] treated 35 BD I and II depressed patients with a HAMD of > 18 with valproate loading doses (target plasma level: 50–100 μg/ml) and subsequently randomized the patients to receive either 1 g twice daily of purified cytidine or placebo over 12 weeks. From weeks 1–4, there were statistically significant differences in HAMD score favoring the cytidine group. However, these differences were no longer significant from weeks 6–12, and at endpoint, the response rates did not significantly differ (cytidine: 53.3%, placebo: 46.6%, P = .85). There were no statistically significant differences between the groups in the frequency of adverse events. N-acetylcysteine (NAC). NAC consists of the amino acid cysteine combined with an acetyl group. It has anti-inflammatory and antioxidant properties and modulates CNS glutamate and dopamine levels.[42] Berk et al.[43] enrolled 75 BD I and II subjects in any mood state (27 depressed) who had experienced 1 mood episode in the last 6 months and randomized them to receive 24 weeks of 2 g per day of NAC or placebo in addition to treatment as usual. Thirty-six percent of the sample was in a depressive episode at baseline. At week 24, NAC was associated with a significant reduction in MADRS scores (least squares mean difference = –8.05, P = .002). Response rates (defined as ≥ 50% reduction from baseline MADRS score) at week 24 were 51% for the NAC group and 18% for the placebo group. There were no differences between the groups for time to a new mood episode, or number of new episodes of depression or mania. During poststudy follow up, when NAC had been discontinued, the benefits of NAC did not persist. There were no statistically significant differences in adverse events between the two groups. Unfortunately, the authors did not separately report the efficacy results and dropout rates for the subjects who were in a major depressive episode at study baseline, leaving the benefit of NAC for BD depression unresolved. Berk et al.[44] reported another study of NAC, enrolling 149 BD type I, II, and NOS subjects with a MADRS ≥ 12. All patients received open-label NAC 2

383

g per day for 8 weeks and then were randomized to continued NAC treatment or placebo for an additional 24 weeks. Among those receiving NAC, 37.3% developed a depressive episode as compared to 48.4% of those receiving placebo, (P = .147). The average time to a new full depressive episode also favored those in the NAC group (170 ± 12.8 days) as compared to those in the placebo group (137.4 ± 10.4), though this difference was not significant (P = .341). The mean MADRS score change was also not significantly different between the groups. There were more manic episodes in the NAC group (11.9%) than in the placebo group (3.2%) though this also was not statistically significant (P = .07). Adverse events were not reported. Inositol. Inositol is a glucose isomer and a precursor in the phosphatidyl-inositol secondary messenger pathway activated by various neurotransmitters.[45] In the first randomized controlled trial using inositol, Levine et al.[46] found no benefit for inositol (12 g/d) over glucose given for 4 weeks to 28 patients in a major depressive episode, including six lithium-refractory BD patients. Two patients in the inositol group reported adverse events not seen in the glucose group, nausea (n = 1) and flatus (n = 1). Two subsequent studies also found no benefit on continuous outcome depression measures, but responder analyses provided partial support of efficacy. Chengappa et al.[47] randomized 24 BD I or II depressed patients refractory to mood stabilizer to either adjunctive inositol 4 g three times daily or placebo for 6 weeks. Numerically more patients responded to inositol (50%) than placebo (30%) (P > .05), defined as ≥ 50% reduction in the baseline HAMD score and a CGI-I ≤ 2 at week 6. Of the six inositol responders, five maintained their response throughout a 24-week posttreatment follow up period. Twenty-five percent of inositol patients experienced loose stools as compared to 8% of placebo patients. Two of three patients in the inositol group experienced a reduction in baseline tremor, while neither of the two patients with hand tremors in the placebo group experienced a reduction in their tremor. Evins et al.[48] enrolled 18 BD depressed I or II subjects who had at least 2 weeks of therapeutic levels of lithium (>0.8 mEq/L) or valproate (>50 mg/L). Patients were randomized to receive either inositol up to 19 g daily or placebo for 6 weeks. Notably, the inositol group baseline HAMD score was significantly lower than the placebo group’s (17.9 ± 3.1 vs. 22.1 ± 3.27, P = .015). Among those receiving inositol, 44% of subjects were responders (defined as: 50% reduction from baseline on the HAMD and CGI-I ≤ 2) whereas no subjects receiving placebo met response criteria, (P = .053, 1-sided t-test). Six subjects in the inositol group continued receiving inositol in an open-extension phase. Five either improved further or remained stable while one worsened clinically. There were no differences in the number of adverse events reported between the two treatment groups. As part of the Systematic Treatment Enhancement Program for Bipolar Disorder, 66 BD type I or II depressed patients in a major depressive episode were Depression and Anxiety

Depression and Anxiety

Inositol Levine (1995)

Berk (2012)

N-acetylcysteine (NAC) Berk (2008)

Cytidine Yoon (2009)

Author (year)

Type I, depression

Type I, II and NOS depression, MADRS ≥ 12

Type I and II, had at least 1 mood episode in the last 6 mos, euthymic: 49% depressed: 36% Manic: 15%

Type I and II, depressed, HAMD > 18

Study sample

13.1 ± 9.7 12.2 ± 9.9 (MADRS)

NAC 2 g/d (N = 76) PBO (N = 73)

PBO-glucose (N = 2)

NR

13.3 ± 9.3 (MADRS)

PBO (N = 37)

Inositol 12 g/d (N = 4)

16.6 ± 11.7

23.1 ± 2.0 (HAMD)

PBO-fructose + VPA (N = 17)

NAC 2 g/d (N = 38)

23.3 ± 2.3

Baseline severity

Cytidine 1g BID + VPA (N = 18)

Treatment arms/ (N bipolar)

Yes, benzodiazepines only

Yes

Yes

No

Adjunctive psychotropic treatments allowed

TABLE 3. Randomized controlled trials of nonessential nutrients for bipolar depression

No

Yes, for the 1st month only

No

N/A

Adjunctive psychotropic treatments held constant

4 wks

24 wks

24 wks

12 wks

Duration

Continued.

HAMD change: inositol: 14.3 ± 8.3, PBO: 14.5 ± 4.9, P = NR.

MADRS endpoint score: NAC lower than PBO at wks 20 and 24, P = 0.002 MADRS response rates at 24 wks: NAC: 51%, PBO: 18%, P = .001 Proportion experiencing depressive episode: NAC: 37.3%, PBO: 48.4%, P = NS Mean change on MADRS: NAC: 0.6 ± 1.5, PBO: 1.5 ± 1.5, P = NS Average survival time to a new depressive episode: NAC: 170 ±12.8 days, PBO: 137.4 ± 10.4 days, P = NS

HAMD difference: no difference at endpoint significant differences from wks 1–4 only Response rates: cytidine group: 53.3%, PBO group: 46.6%, P = NS

Depression outcomes:

384 Rakofsky and Dunlop

Type I and II, depression, HAMD ≥ 15, and refractory to mood stabilizers

Type I and II, depression, HAMD ≥ 15 × 2 visits while on Li or VPA

Types I and II, depression, ≥ 8 wks, unresponsive to standard or randomized care pathway, or failed ≥ 2 ADs or an AD and MS

Chengappa (2000)

Evins (2006)

Nierenberg (2006)

20.3 ± 4

20.8 ± 5.7 (HAMD)

17.9 ± 3.1

22.1 ± 3.3 (HAMD, P = .015)

Inositol 12 g /d (N = 12)

PBO-D-glucose (N = 12)

Inositol, 19 g/d max (N = 9)

PBO-Lactose (N = 8)

7.7 ± 3.5

Inositol 10–25 g/d (N = 23) RIS 6 mg max (N = 22)

6.3 ± 3.5 (SUM-D)

7.0 ± 3.4

LTG 150–250 mg/d (N = 21)

(MS + 1–2 ADs +...)

Yes

Baseline severity

Yes

Yes

Adjunctive psychotropic treatments allowed

Treatment arms/ (N bipolar)

No

Yes

NR

Adjunctive psychotropic treatments held constant

16 wks

6 wks

6 wks

Duration

Percent with 50% decline on HAMD and CGI-I ≤ 2: inositol: 50%, PBO: 33%, P = NS 50% decline on MADRS: inositol: 67%, PBO: 33%, P = NS HAMD differences between groups: P = NS 5/6 Inositol responders maintained response × 24 wk open extension phase Percent with 50% decline on HAMD and CGI-I ≤ 2: inositol: 44%, PBO: 0%, P = .053, 1-sided t-test No statistically significant differences on HAMD at wk 6 5/6 inositol subjects improved or remained stable during open extension phase Recovery: no more than two symptoms meeting DSM-IV mood episode criteria and no significant symptoms present for 8 weeks. Within equipoise strata: LTG: 16.7% vs. RIS: 9.1%; LTG: 26.7% vs. Inositol: 12.5%; RIS: 7.7% vs. Inositol: 37.5%; P > 0.10 for all comparisons Across equipoise strata: LTG: 28%, Inositol: 17.4%, RIS: 4.6%, P = NR

Depression outcomes:

AD, antidepressant; HAMD, Hamilton depression scale; LTG, lamotrigine; MADRS, Montgomery–Asberg depression scale; Max, maximum; MS, mood stabilizer; NA, not applicable; NOS, not otherwise specified; NR, not reported; NS, not significant; PBO, placebo; RIS, risperidone; SUM-D, sum of all associated symptoms on the clinical monitoring form; VPA, Valproate.

Study sample

Author (year)

TABLE 3. Continued

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randomized to 16 weeks of open-label treatment with adjunctive lamotrigine, inositol, or risperidone.[49] All patients had demonstrated poor response to 12 weeks of a standard or randomized care pathway, or had a history of failure to respond to at least two antidepressants or an antidepressant plus mood stabilizer. Subjects assigned to lamotrigine had significantly lower SUM-D (the sum of depressive symptoms listed on the Clinical Monitoring Form) and CGI scores and higher GAF scores compared to those receiving inositol or risperidone. The overall recovery rate was 23.8% for lamotrigine, 17.4% for inositol, and 4.6% for risperidone (no significance testing performed). Inositol-treated patients remained in the study significantly longer than those assigned to risperidone and there were no differences in the number of adverse events reported between the three treatment groups. Summary. Among nonessential nutrients studied in RCTs, cytidine is the least supported treatment. Studies of NAC have not resolved its efficacy in treating acute depressive episodes relative to placebo. However, one study demonstrates its potential to improve depressive symptoms over time and the other, though nonsignificant, suggests it has a prophylactic effect. Studies of inositol have been mostly negative, except for one study. Those that were negative were underpowered but demonstrated numerically positive effects for inositol. COMBINATIONS

Table 4 presents the summary data of randomized, controlled trials of combination nutritional products. O3FAs and Cytidine. In a randomized controlled trial of 45 BD I outpatients,[50] the combination of O3FAs (3 g EPA/day) plus cytidine (2 g/day), was compared against O3FAs alone or placebo alone for 16 weeks. All patients had experienced a mood episode during the previous year (episode polarity unreported) and were on a stable medication regimen for at least 2 weeks prior to randomization. The three groups did not differ significantly on the primary outcome (study retention) hazard ratios, though dropout was least common in the placebo group (O3FA-alone, HR = 1.72, 95% CI: 0.5–5.91; O3FA-CYT, HR = 1.91, 95% CI: 0.54–6.83, P = ns). The three groups also did not significantly differ in symptoms of depression or mania or GAF scores. The most common adverse event reported was mild gastrointestinal distress however no comparison between the groups for this adverse event or others was reported. Citicoline. Citicoline is cytidine-5 -diphosphocholine and is rapidly metabolized to cytidine and choline after oral ingestion, two nutrients that have both demonstrated potential benefits in bipolar depression.[41, 51] The combination increases neurotransmitter levels, enhances synthesis of structural phospholipids, and prevents cell death.[52] Two randomized controlled trials performed by the same group have evaluated its efficacy in substance abusing patients with mood disorders. No randomized controlled trials Depression and Anxiety

using this compound have been performed in BD patients without substance abuse. In the first randomized controlled trial, Brown et al.[53] evaluated 60 mood-disordered subjects (BD depression I, II, NOS (n = 17); MDD n = 43), with methamphetamine dependence and recent methamphetamine use. Patients were randomized to 12-weeks of add-on treatment with citicoline up to 2 g/d versus placebo. Compared to placebo, those receiving citicoline had a greater decrease in baseline to exit scores on the IDS-CR, (P = .05), longer survival in treatment (P = .02), higher completion rates (P = .02), but no difference in methamphetamine use or in memory as measured with the Hopkins Auditory Verbal Learning Test. Side effects scores were significantly lower in the citicholine group. The second randomized controlled trial evaluated the efficacy of citicholine dosed up to 2 g/d versus placebo over 12 weeks in cocaine abusing or dependent patients with either BD disorder I, II (n = 39) or schizoaffective disorder-BD type (n = 5).[54] Although there were no difference on the IDS-self report scale between the groups, those receiving placebo had a 6.41 (95% CI: 1.3–33.3) greater odds of testing positive for cocaine at the exit visit and performed worse on the Rey Auditory Verbal Learning Test alternative word list (P = .006). Adverse events occurring with greater frequency in the citicholine group include diarrhea, insomnia, decreased appetite, increased sleep, nausea and constipation. No statistical comparisons of adverse events between groups were reported. Summary. There is no evidence that citicholine is efficacious for uncomplicated BD depression, though it may have value for comorbid substance abuse among BD patients. Combination O3FA-cytidine lacks evidence of efficacy.

DISCUSSION This review did not find definitive evidence of benefit for any nutritional supplement for the treatment or prevention of bipolar depression. Nutritional supplements such as O3FAs, vitamin C, NAC, inositol, or citicholine, for which more than one study was conducted, demonstrated inconsistent results. Folic acid, choline, and O3FA-cytidine have no evidence of efficacy from randomized controlled trials. Unfortunately, many of these studies were underpowered and some suffered limitations from their methodologic design, as discussed below. For treating acute BD depression, the study with the best design and thus for which conclusions can be most solidly drawn, was the evaluation of inositol conducted by Evins et al.[48] This study of BD depressed I and II patients lasted 6 weeks, tested high dose inositol, required a minimum HAMD severity for entry, and allowed adjunctive medications to be used but required them to be unchanged during the study. Although the sample

Type I, II, or schizoaffective-bipolar type, index mood episode NR Last cocaine use 1–12 wks before study entry

37.8 ± 2.3 (IDS-C) 43.6 ± 10.6 38.7 ± 13.0 (IDS-SR)

PBO (N = 20)

PBO (N = 21)

Citicoline 2g (N = 23)

38.8 ± 1.5

NR

Baseline severity

Citicoline 2 g (N = 28)

EPA 3 g/d-PBO (N = 15) PBO-PBO (N = 15)

Had a mood episode during the previous year

Type I, II, NOS depression, methamphetamine use within 14 days prior to baseline

EPA 3 g/d-CYT 2 g/d (N = 15)

Type I, index mood episode NR,

Study sample

Yes

Yes

Yes

Adjunctive psychotropic treatments allowed

No

No

Yes

Adjunctive psychotropic treatments held constant

12 wks

12 wks

16 wks

Duration

No between group differences on the IDS-SR

Compared to PBO group, citicoline group had greater decrease in IDS-C score, P < .05

(1) Odds of symptoms of depression: EPA only, 3.93 (0.78–19.67) EPA/CYT, 3.24 (0.77–13.56) (2) Estimated mean log MADRS scores: EPA only, 1.19 (0.64–2.21) EPA/CYT, 1.17 (0.63–2.17)

No differences between groups in change in the probability of symptoms of depression, or change in positive ratings of depression Compared to PBO:

Depression outcomes:

CYT, cytidine; EPA, eicosopentaenoic acic; RCT, randomized control trial; MADRS, Montgomery–Asberg depression scale; PBO, placebo; NA, not applicable; NR, not reported; NS, not significant; NOS, not otherwise specified; O3FA, omega 3 fatty acids; IDS-SR, inventory of depressive symptoms-self report; N, sample size.

Brown (2007)

Citicoline Brown (2012)

Omega-3 Fatty Acids plus Cytidine Murphy (2012)

Author (year)

Treatment arms/ (N bipolar)

TABLE 4. Randomized controlled trials of nutrient combination products for bipolar depression

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size was small, the 24-week extension allowed for observation of continued benefit in those who had acutely responded. These are partially supported by the results from the STEP-BD study of inositol by Nierenberg et al.[49] Although inositol was inferior to lamotrigine, a well-established prophylactic treatment for BD depression, it produced numerically greater recovery rates than risperidone. The absence of placebo in this trial prohibits definitive conclusions about the acute efficacy of inositol for BD depression, but there is certainly sufficient evidence to warrant further evaluation. Among the studies examining prophylactic effects for mood episodes, Coppen et al.[31] used the most rigorous design. In that study, euthymic BD patients attending a lithium clinic received folic acid or placebo in addition to lithium and were followed for up to a year. The study’s negative results may have stemmed from including patients with a low likelihood of depressive recurrence over a year’s time or from using a dose of folic acid less than the recommended daily allowance.[55] Unfortunately, design limitations for both the positive and negative studies reduce the confidence with which conclusions about efficacy can be drawn. Many of the acute treatment studies had a long duration (up to 4 months) that may have allowed for patients to experience a natural recovery from their episode, thus diminishing any drug-placebo difference. Sample sizes were often small, increasing the chances of both false positive and false negative outcomes. Baseline mood symptom severity and/or episode were often not reported, thereby allowing potentially confounding baseline differences to be present between the randomized groups. Some studies included patients in any mood episode, making it unclear for which illness pole the study compound was most effective. For some supplements, particularly O3FAs, unblinding of participants or raters may have occurred due to the supplements’ unique tastes. Adjunctive psychotropic medication changes were allowed during the randomized controlled trial in some studies, confounding the interpretation of the study outcome. Finally some included patients with very low symptom severity, leaving little room for demonstrating the supplement’s benefit due to floor effects. Other reviews have also identified limitations to the acute efficacy trial data. The Cochrane Database Review focused exclusively on one supplement, O3FAs.[20] That review found only one of five eligible studies provided sufficient data for metaanalyses, as it was the only one that provided complete results from an intention to treat analysis. This one study[25] was the basis for the tenuous support the authors provided for O3FA use in BD depression and the authors identified significant areas of concern for the other four studies. On the other hand, a metaanalysis[21] of five placebo-controlled O3FA trials revealed a significant effect favoring O3FAs, though the effect size was only moderate (0.34) and the metaanalysis may have combined a heterogeneous population of BD patients. Two qualitative reviews[17, 19] both Depression and Anxiety

concluded that current evidence only weakly supports use of O3FAs and an effect size analysis of studies adding O3FAs to standard BD phamacotherapies[18] concluded that there were mixed results for O3FA. Other analyses in that same review[18] revealed large effect sizes for NAC and a chelated mineral and vitamin formula in the treatment of BD depression, though, again, design limitations limit the confidence in the reported effect sizes. The chelated mineral and vitamin formula was excluded from our review as there have been no published RCTs that have studied its effect. In the review of complementary and alternative medicine treatments for BD,[17] O3FA’s, folic acid, NAC, and others are suggested as adjuncts to mood stabilizer and antipsychotics, however, based on our analysis of the literature, such conclusions should be reconsidered. Many of these critiques apply to the prophylactic studies as well. However, in these studies, the study duration was often too short. Four months is an insufficient period to detect an appreciable difference in episode prevention between two treatments. Additionally, the failure to include patients with a mood episode within the last year can result in a low likelihood of recurrence during the course of the study, making a drug-placebo difference unlikely. Nutritional supplements have been incorporated into a few BD depression treatment algorithms. The Texas Medication Algorithm Project for BD depression lists the addition of inositol as the 5th step in its algorithm.[56] The American Psychiatric Association Treatment Guidelines for Bipolar depression indicate that O3FA’s require further study.[57] The Canadian Network for Mood and Anxiety Treatments and International Society for Bipolar Disorders collaborative treatment guidelines for BD list EPA and NAC under the heading “novel/experimental treatments” as a 5th step in its depression algorithm.[58] Given that there is such weak evidence for the efficacy of the majority of these products, their placement at the end of these algorithms, after agents with better efficacy have been initiated and combined with one another, is appropriate and consistent with our analysis. Future studies of nutritional supplements will need greater rigor in design in order to convincingly demonstrate efficacy. Statistical analyses should include preplanned subgroup analyses of patients hypothesized to have the best chance of benefit from a supplement, e.g. those with specific nutritional deficiencies. Synergistic mood stabilizer-supplement interactions should also be evaluated to determine if the therapeutic potential of a mood stabilizer can be enhanced by a supplement that carries a low risk of adverse effects. Metabolomic or gene expression measures can be incorporated into such studies to determine predictors and mediators of response that might help guide treatment selection. Finally, there are several other supplements, including chromium,[59] magnesium,[60] multinutrient formula,[61] and triacetyluridine[62] that have not

Review: Bipolar Depression and Nutritional Supplements

yet been employed in randomized controlled trials, despite case series suggesting benefit. 9.

CONCLUSIONS The findings of this review do not support the routine use of nutritional supplements in the treatment or prophylaxis of BD depression. Studies with more rigorous designs are required before definitive conclusions can be made. Although there is likely little medical risk associated with the supplements included in this review, there is a financial cost to the treatments, as well as psychiatric risk stemming from delaying treatment with more proven psychotropic medications. Moreover, some patients may believe a supplement can replace their existing psychotropic regimen and therefore stop taking prescribed medication, placing themselves at increased risk for relapse or significant mood worsening. Communicating this information to patients is of great importance whenever a patient is participating in treatment decisions. It should be noted that patients may derive benefit from some supplements beyond their intended mental health uses, including folate (for the prevention of birth defects), O3FA’s (for lowering triglycerides), and vitamin C (for reducing the severity of cold symptoms). Despite the inadequacy of the existing depression data, clinicians should remain open to the value of nutritional supplements: after all, lithium is a mineral too. Acknowledgments. ments.

There are no acknowledge-

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