The effect of adjunctive nutraceuticals in bipolar disorder: A systematic review of randomized placebo-controlled trials

Journal of Affective Disorders 252 (2019) 334–349

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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Review article

The effect of adjunctive nutraceuticals in bipolar disorder: A systematic review of randomized placebo-controlled trials

T

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Laura Fusar-Polia,b, , Teresa Suracea,b, Antonio Vanellaa,b, Valeria Meoa,b, Federica Pataniaa,b, Rosaria Furnaria,b, Maria Salvina Signorellia,b, Eugenio Agugliaa,b a b

Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, Italy U.O.C. Clinica Psichiatrica, A.O.U. Policlinico-Vittorio Emanuele, Presidio “G. Rodolico”, Catania, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords: Bipolar disorder Depression Mania Nutraceuticals Fatty acids Systematic review

Background: Nutraceuticals are a group of compounds of growing interest for mental health professionals. Given the implication of certain nutrients in the onset of bipolar disorder, it has been hypothesized that nutraceuticals might be effective in improving symptoms of the condition (i.e. mania or depression). Our systematic review aimed to evaluate the effectiveness of adjunctive nutraceuticals compared to placebo. Methods: We searched the following databases from inception to February 2019: Web of Science, CINAHL, Embase, and PsycINFO. We included only original randomized controlled trials written in English, testing the efficacy of nutraceuticals in add-on to standard care, compared to placebo, in patients with bipolar disorder. Results: After identifying 6584 potentially relevant publications, we finally included 25 studies, among which six used fatty acids, seven micronutrients, seven amino acids. One study tested probiotics, while in four trials a combination of different types of nutraceuticals was used. Even if some compounds have shown promising results (i.e. fatty acids and N-acetyl cysteine for depression, amino acid drinks and folic acid for mania), the majority of nutraceuticals did not cause significant improvements in comparison to placebo. Limitations: We could not perform a meta-analysis due to the high heterogeneity of trials, which were also affected by some methodological caveats. Conclusions: Evidence regarding the efficacy of adjunctive nutraceuticals in bipolar disorder is inconsistent. Nevertheless, they appear generally free from relevant side effects. Well-designed trials are needed to further explore the potential role of nutraceuticals in different mood episodes.

1. Introduction Bipolar disorder (BD) is a psychopathological condition with a multifactorial etiology, consisting in episodes of severe mood disturbances associated with neuropsychological deficits and severe functional impairment. As reported by recent epidemiological evaluations, lifetime prevalence of BD is estimated around 1–2% (Merikangas et al., 2011). According to the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar and related disorders include bipolar I disorder, bipolar II disorder and cyclothymic disorder (American Psychiatric Association, 2013). Additionally, bipolar-like phenomena that do not fulfill the diagnostic criteria for a specific BD are categorized under the label “other specified bipolar and related disorders”. While diagnosing and treating BD, it is also important to specify the characteristics of current mood episode (i.e. mania, hypomania or depression) (American Psychiatric

⁎

Association, 2013). BD is an important cause of disability and it is also associated with high rates of premature mortality due to both medical comorbidities and high suicide rates (Rowland and Marwaha, 2018). Accordingly, millions of people affected by BD adhere to pharmacological treatments during the lifespan in order to prevent recurrence or relapse of mood episodes (Joas et al., 2017). Potential long-term side effects of recommended psychotropic drugs, such as mood stabilizers (i.e. lithium, sodium valproate) or antipsychotics (i.e. olanzapine, quetiapine) include renal, thyroid and parathyroid dysfunctions, hepatic malfunction up to serious hepatic failure, and metabolic syndrome (Correll et al., 2015; Gitlin, 2016; Hayes et al., 2016). Experiencing such side effects may reduce patients' adherence to treatment (García et al., 2016). Consequently, research has been focusing on the assessment of alternative therapeutic approaches in order to identify safer strategies for the enhancement of medication effects in patients with BD (Sarris et al.,

Corresponding author at: Department of Clinical and Experimental Medicine, Psychiatry Unit, University of Catania, via Santa Sofia 78, 95123 Catania, Italy. E-mail address: [email protected] (L. Fusar-Poli).

https://doi.org/10.1016/j.jad.2019.04.039 Received 31 January 2019; Received in revised form 11 March 2019; Accepted 7 April 2019 Available online 08 April 2019 0165-0327/ © 2019 Elsevier B.V. All rights reserved.

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2. Methods

2016). Nutraceuticals represent a common form of adjunctive treatment to pharmacological therapy. A nutraceutical can be defined as “food or part of a food that provides medical or health benefits, including the prevention and/or treatment of a disease” (DeFelice, 1995). Nutraceuticals differ from pharmaceuticals mainly because they lack a shared regulatory framework; in general, they do not need a process of approval of their safety and efficacy (Santini et al., 2018). Over the last years, a rapid increase in the use of nutraceuticals among psychiatric patients has been reported, for instance among people suffering from depression, anxiety (Abed et al., 2018) or dementia (Qato et al., 2016), with a consequent potential misuse (Schifano et al., 2015) or inappropriate use (Qato et al., 2016) of these substances. However, it has been shown that the use of nutraceuticals in add-on to standard therapy may improve symptomatology, thus allowing patients to take lower doses of common psychiatric drugs and ameliorating their compliance with pharmacological therapy (Santini et al., 2017). The use of nutraceuticals as adjuvants is supported by several studies that have reported that patients with mood disorders, including BD, may show deficient levels of certain nutrients (Belzeaux et al., 2015). For instance, some studies have found lower concentrations of fatty acids (Chiu et al., 2003; Pomponi et al., 2013; Su et al., 2015), vitamin D (Boerman et al., 2016), zinc (Siwek et al., 2016), magnesium (Nechifor et al., 2006), and inositol (Chengappa et al., 2000) in patients with BD than healthy controls. Additionally, some authors have hypothesized that oxidative stress would be increased (Ellegaard et al., 2018) and antioxidant levels decreased (De Berardis et al., 2008) in patients with BD. Also, potential roles of cholesterol (De Berardis et al., 2009) and inflammation (De Berardis et al., 2006) in the etiology of mood disorders have been argued. Recently, Evans et al. (2017) found that the composition of gut microbiome significantly differed between subjects with BD and controls. Guidelines for the management of BD (Goodwin et al., 2016; Grunze et al., 2013; Kendall et al., 2014) do not suggest nutraceuticals as potential therapeutic agents for BD, neither in the acute phase nor in the long-term treatment. However, the unbalanced levels of some nutrients, as well as the presence of high levels of oxidative stress and inflammation in subjects with BD, have led to hypothesize their potential role in the development of the disease. Therefore, researchers have started to theorize that nutraceuticals may play a beneficial role when added to standard pharmacological therapy. Several reviews have tried to summarize available literature regarding the use of nutraceuticals in mood disorders, such as BD. For instance, a recent meta-analysis (Sarris et al., 2016) supports the adjunctive use of S-adenosylmethionine, methyl folate, omega-3, and vitamin D with antidepressants to reduce depressive symptoms. With regard to mood disorders more broadly, a recent narrative review reported that omega-3 would be effective in addition to normal drug therapy in both unipolar and bipolar depression, while NAC would be effective only in bipolar depression (Sarris, 2017). To our knowledge, in the last published metaanalysis specifically focused on nutraceuticals for BD, Sarris et al. (2011) reported on the one hand the efficacy of NAC and a chelated mineral and vitamin formula on depression; on the other hand, a chelated mineral formula, L-tryptophan, magnesium, folic acid, and branched-chain amino acids seemed effective on mania (Sarris et al., 2011). However, results often relied on single trials, not always randomized, and including participants experiencing different mood episodes, thus hampering the generalizability of findings. Accordingly, given the potential benefits of nutraceuticals in mood disorders, as well as the growing interest about their use in mental health, we aimed to provide an up-to-date review to summarize all randomized placebocontrolled trials evaluating the efficacy of nutraceuticals as add-on therapy in BD.

The protocol was registered on PROSPERO, an international database of prospectively registered systematic reviews in health and social care managed by the Centre for Reviews and Dissemination, University of York (Registration number: CRD42018114734). 2.1. Search strategy We performed a systematic search following the PRISMA Statement guidelines (Moher et al., 2009). We search the following databases from inception to February 2019: Web of ScienceSM (including Web of Science, MEDLINE®, KCI – Korean Journal Database, Russian Science Citation Index and SciELO Citation Index), CINAHL, Embase, and PsycINFO. The search was not restricted to any language, reference type, or year of publication. We adopted the following search strategy: (bipolar OR mania OR "mood disorder*" OR hypomania OR cyclothymia) AND (nutraceutical* OR omega-3 OR "omega 3″ OR "fatty acid*" OR vitamin* OR mineral* OR "amino acid*" OR inositol OR "folic acid" OR magnesium OR zinc OR "flaxseed oil" OR probiotic* OR prebiotic* OR tryptophan OR "acetyl cystein") AND (trial* OR RCT OR randomized OR randomised OR experimental). The electronic search was supplemented by hand-searching of reference lists of all included systematic reviews and meta-analyses to identify additional articles. 2.2. Selection procedure All records were extracted to EndNote reference management software. Duplicates were detected and deleted. Two researchers (AV and FP), working independently and in duplicate, screened titles and abstracts to identify potentially relevant studies and assessed full-texts to determine eligible studies. Any doubt was solved through consultation with a third reviewer (LF). We included all original articles written in English which met the following criteria: (1) Participants: individuals with bipolar disorder (type I or type II), mania or schizoaffective disorder, bipolar type, diagnosed by a clinician according to international valid diagnostic criteria (i.e. DSM or ICD). (2) Intervention: nutraceuticals of any type, dosage and form of administration (i.e. omega 3 fatty acids, vitamins, minerals, amino acids, N-acetyl cysteine, probiotics, etc.), in combination with standard care. (3) Comparison: placebo plus standard care. (4) Outcomes: depressive symptoms or manic symptoms, evaluated through standardized measures, clinical global impression, functioning, adverse events, other outcomes. (5) Study design: randomized controlled trials, both parallel and crossover. 2.3. Data collection and extraction process Two review authors (VM and TS), working independently and in duplicate, extracted data and assessed trials for risk of bias following the Cochrane risk of bias tool (Higgins et al., 2011). Any doubt was solved through consultation with a third reviewer (LF). A standardized form was used to extract data from the included studies, for assessment of study quality and evidence synthesis. We extracted information about study characteristics, sample characteristics, type and duration of the interventions, outcomes and side effects. 2.4. Data synthesis We have provided a narrative synthesis of findings according to the types of nutraceuticals, based on the following categories: (a) fatty 335

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Fig. 1. PRISMA flow diagram of selection process.

duplicates, 5411 titles and abstracts were screened. Full-texts of 156 articles were fully read for a more detailed evaluation. Finally, 25 papers were included in the systematic review. Reasons for exclusion have been explained in the PRISMA flow-chart (Fig. 1).

acids, (b) micronutrients, (c) amino acids and derivatives, (d) combinations of different nutraceuticals, (e) probiotics. Results for each category have been presented according to the following outcomes: depression, mania, clinical impression, functioning, adverse events, other outcomes. Even if initially planned, given the heterogeneity of trials, participants, and intervention characteristics, we did not consider methodologically correct to perform a meta-analysis.

3.2. Fatty acids 3.2.1. Study characteristics We found six studies evaluating the effectiveness of fatty acids compared to placebo. Three studies had a duration of 12 weeks, while the other three had a length of 16 weeks. All trials had a parallel group design. Randomized samples varied from 11 (Fristad et al., 2015) to 116 (Keck et al., 2006) participants. Study design was parallel group for all RCT. Studies were conducted in the United States, Germany, Canada, United Kingdom or Iran (Table 1).

3. Results 3.1. Search results Our literature search identified a total of 6579 publications, while five further potentially relevant publications were obtained from references lists of included reviews and meta-analyses. After removing 336

337

Germany, United States

Stoll et al., 1999

Parallel

Parallel

Parallel

Parallel

Parallel

Parallel

Design

Bipolar I and II and rapid cycling disorder (DSM-IV)

Bipolar I (DSM-IVTR)

Bipolar I or II (DSMIV)

Subsyndromal bipolar disorder and cyclothymic disorder (DSM-IV). Comorbidities: anxiety ADHD, disruptive behavior disorders Bipolar I and II (DSM-IV)

Bipolar I and II (DSM-IV)

Mania or combination state Depression, hypomania, mania, euthymia

Depression, mania or hypomania

Depression, mania, mixed

Depression, mania

Depression

Participants characteristics Type of diagnosis Episode (tool)

43 (24–64)

37.9

46.5 (20–73)

11.5 (6–17)

10.5 (7–14)

44 (18–70)

Mean age (range)

54

100 (50,50)

116 (59, 57)

51

11 (5, 6)

75 (49, 26)

N randomized (active treatment, placebo)

30 (14,16)

100 (50,50)

51

51

9 (4, 5)

70 (47, 23)

N completed (active treatment, placebo)

Omega-3 fatty acids

Omega-3 fatty acids

Ethyleicosapentanoate (EPA), docosahexaenoic acid (DHA)

Flax oil

Omega-3 fatty acids

Ethyleicosapentaenoic acid (EPA)

9.6 g

1g

6.2 g, 3.4 g

12 g

2g

1 g or 2g

Intervention characteristics Type of Daily nutraceutical osage

Carbamazepine, gabapentin, sertraline, lithium, buproprion, alprazolam, clonazepam, divalproex, perphenazine, dextroamphetamine

Lithium, olanzapine

Mood stabilizers

Mood stabilizers, antipsychotics

Medication for ADHD, sleep aids

Lithium, carbamazepine, sodium valproate, antipsychotics, antidepressants, benzodiazepines

Concomitant medication

16

12

16

16

12

12

Duration (weeks)

Depression HDRS + Mania YMRS = Global impression CGI-BP + GAS +

Depression CDRS-R = CPRS = Mania YMRS = Global impression CGI-BP = Functioning GAF = Depression IDS-C = Mania YMRS = Global impression CGI = Mania YMRS +

Depression HDRS+ Mania YMRS = Global impression CGI+ Depression CDRS-R = KDRS + Mania YMRS = KDMS =

Results Outcomes and results

Gastrointestinal problems, loose stools

None

Anxiety, fatigue, bruising, gastrointestinal symptoms, pain, palpitation, headache

Gastrointestinal problems

Constipation, diarrhea, stomachache, belching, fishy breath

Loose stools, gastrointestinal discomfort, constipation, nausea, flatulence

Adverse events

Legend: ADHD: Attention Deficit Hyperactivity Disorder; CDRS-R: Children's Depression Rating Scale; CGI: Clinical Global Impression; CPRS: Comprehensive Psychopathological Rating Scale; DSM: Diagnostic and Statistical Manual of Mental Disorders; GAF: Global Assessment of Functioning; GAS: Global Assessment Scale; HDRS: Hamilton Depression Rating Scale; IDS-C: Inventory Of Depressive Symptomatology; KDRS: Kiddie Schedule for Affective Disorders - Depression; KMRS: Kiddie Schedule for Affective Disorders - Mania; YMRS: Young Mania Rating Scale; +: significant improvement in the active treatment group compared to placebo; =: no significant differences between the two groups.

Iran

Shakeri et al., 2016

United States

Gracious et al., 2010

Germany

United States, Canada

Fristad et al., 2015

Keck et al., 2006

United Kingdom

Frangou et al., 2006

Study characteristics Study Country

Table 1 Effects of fatty acids on symptoms of bipolar disorder.

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3.2.2. Participants’ characteristics As reported in Table 1, one study included only patients with BD I (Shakeri et al., 2016), four studies included patients with BD I or II (Frangou et al., 2006; Gracious et al., 2010; Keck et al., 2006; Stoll et al., 1999), and one trial included subsyndromal BD or cyclothymic disorder (Fristad et al., 2015). In all studies, participants were experiencing different mood episodes, apart from Frangou et al. (2006) that recruited only depressed individuals. Four studies recruited only adult subjects, with age ranging from 18 to 73, and a mean age of 40, while two studies (Fristad et al., 2015; Gracious et al., 2010) recruited children and adolescents. 3.2.3. Intervention characteristics In three studies a combination of different omega-3 fatty acids was used (Fristad et al., 2015; Shakeri et al., 2016; Stoll et al., 1999). In one study, only eicosapentaenoic acid (EPA) (Frangou et al., 2006) was used, while in another one docosahexaenoic acid (DHA) and EPA were tested (Keck et al., 2006). Finally, in one study the treatment was flax oil (Gracious et al., 2010) (Table 1). 3.2.4. Efficacy on depression Depression was measured by means of several different scales, such as the Hamilton Depression Rating Scale (HDRS; Williams, 1988), the Children's Depression Rating Scale-Revised (CDRS-R; Poznanski and Mokros, 1996), the Inventory of Depressive Symptomatology (IDS; Rush et al., 1996) and the Kiddie Schedule for Affective Disorders Depression (KDRS; Chambers et al., 1985). Shakeri et al. (2016) did not use any outcome measures for depression. Positive effects were found only according to Frangou et al. (2006) and Stoll et al. (1999). All the other studies found no significant differences between fatty acids and placebo. 3.2.5. Efficacy on mania Manic symptoms were evaluated with the Young Mania Rating Scale (YMRS; Young et al., 1978) in all studies. Fristad et al. (2015) also used the Kiddie Schedule for Affective Disorders Mania (KMRS; Chambers et al., 1985). No statistically significant differences between the placebo and fatty acid groups were found, except in one trial (Shakeri et al., 2016). 3.2.6. Clinical impression and functioning Clinical global impression was taken into account in four studies, among which two reported significant improvements in the fatty acids group (Frangou et al., 2006; Stoll et al., 1999), while two did not detect any significant differences (Gracious et al., 2010; Keck et al., 2006). Of note, Stoll et al. (1999) did not use only Clinical Global Impression (CGI; Spearing et al., 1997), but also the Global Assessment Scale (GAS; Endicott et al., 1976). Functioning was measured only by Gracious et al. (2010), that did not find any significant improvement at Global Assessment of Functioning (GAF; Jones et al., 1995). 3.2.7. Adverse events In general, study medication was well tolerated; no significant differences were found between the two groups. All studies reported gastrointestinal distress, apart from one trial (Shakeri et al., 2016). 3.2.8. Risk of bias According to the Cochrane's tool four studies had adequate random sequence generation (Frangou et al., 2006; Fristad et al., 2015; Gracious et al., 2010; Keck et al., 2006), while Shakeri et al. (2016) and Stoll et al. (1999) did not provide sufficient information and were then rated as unclear. Three trials had a low risk of bias for the allocation concealment (Frangou et al., 2006; Gracious et al., 2010; Keck et al., 2006), while the other trials had an uncertain allocation concealment. All studies had an adequate blinding of participants, personnel and outcome assessors. Risk of attrition bias was low in all the included 338

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Fig. 2. Risk of bias of trials testing the effect of (a) fatty acids, (b) micronutrients, (c) amino acids and derivative compounds, (d) combinations of nutraceuticals, (e) probiotics. Legend: green (+) = low risk of bias; yellow (?) = unclear risk of bias; red (−) = high risk of bias. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

3.3.6. Clinical impression, general psychiatric symptoms, and anxiety CGI was used by Chengappa et al. (2000) and Evins et al. (2006), who did not find significant differences between active treatment and placebo. Giannini et al. (2000) adopted as unique outcome measure the Brief Psychiatric Rating Scale (BPRS; Overall and Gorham, 1962), finding significant improvements after the administration of magnesium. Marsh and colleagues (Marsh et al., 2017) evaluated anxiety symptoms after the use of vitamin D, but no clinical efficacy was detected.

studies, apart from Stoll et al. (1999) that used a per protocol analysis. Selective reporting was considered at low risk in all trials (Fig. 2a).

3.3.7. Adverse events In Behzadi's trial (Behzadi et al., 2009), cases of severe rashes and agranulocytosis were reported. Mehrpooya et al. (2018) reported epigastric issues and sleep impairments. No other clinically relevant adverse events were experienced by patients.

3.3. Micronutrients 3.3.1. Study characteristics We finally included seven articles evaluating the efficacy of micronutrients, defined as essential elements required by organisms in small quantities. Duration of trials varied from two days (Naylor and Smith, 1981) to 16 weeks (Giannini et al., 2000). Study design was parallel group for all RCTs, except from Naylor's trial (Naylor and Smith, 1981) that had a crossover design. Randomized sample sizes ranged from 10 (Giannini et al., 2000) to 89 (Mehrpooya et al., 2018). The majority of studies were conducted in the United States, while two studies were conducted in Iran (Behzadi et al., 2009; Mehrpooya et al., 2018), and one in the United Kingdom (Naylor and Smith, 1981) (Table 2).

3.3.8. Risk of bias Only Marsh et al. (2017) and Mehrpooya et al. (2018) provided sufficient information about randomization procedure and allocation concealment and were considered at low risk of bias in both domains. On the contrary, the other trials did not provide sufficient information, and were thus rated as unclear. Concerning blindness, only two studies (Giannini et al., 2000; Naylor and Smith, 1981) did not specify if participants and personnel were blind to the type of treatment received, while outcome assessors were blind in all studies, apart from one trial (Naylor and Smith, 1981). Attrition bias was rated as unclear in three studies (Behzadi et al., 2009; Chengappa et al., 2000; Giannini et al., 2000) and at high risk of bias in one study (Mehrpooya et al. (2018), since a per protocol analysis was conducted. Reporting bias was unclear in two trials (Chengappa et al., 2000; Evins et al., 2006). The study by Naylor and Smith (1981) was at high risk for both attrition and reporting bias. We considered the study by Chengappa and colleagues (Chengappa et al., 2000) also at high risk for other bias, because inositol was purchased from a pharmaceutical company (Fig. 2b).

3.3.2. Participants’ characteristics All trials included adult subjects with a diagnosis of BD I or II, with mean ages ranging from 22 to 45 years. In four studies (Chengappa et al., 2000; Evins et al., 2006; Marsh et al., 2017; Mehrpooya et al., 2018) patients were in depressive phase of BD, in other two (Behzadi et al., 2009; Giannini et al., 2000) they were experiencing hypomania or mania. Notably, participants of the study by Naylor and Smith (1981) had a diagnosis of manic or depressive psychosis (Table 2).

3.4. Amino acids and derivative compounds 3.3.3. Intervention characteristics As reported in Table 2, in two studies researchers administered inositol (vitamin B7) in add-on to standard therapy (Chengappa et al., 2000; Evins et al., 2006). In one study the active treatment was represented by folic acid (Behzadi et al., 2009), while vitamin D (Marsh et al., 2017) and magnesium (Giannini et al., 2000) were administered in one trial each. One recent study administered coenzyme Q10 (Mehrpooya et al., 2018) in add-on to standard treatment. Finally, Naylor and Smith (1981) administered vitamin C (vanadium) as active treatment.

3.4.1. Study characteristics Seven studies were included in this section. Duration of trials varied from one (Applebaum et al., 2007; Scarna et al., 2003) to 24 weeks (Berk et al., 2008, 2012; Magalhães et al., 2011). Of note, Berk et al. (2012) was an 8-week open-label study followed by a randomized phase; only the second part of the study was considered in the present review. All studies were parallel group RCTs and were conducted in different countries. Randomized sample sizes ranged from 17 (Magalhães et al., 2011) to 101 (Berk et al., 2012). Data regarding this group of studies are reported in Table 3.

3.3.4. Efficacy on depression Depressive symptoms were measured in four studies, by means of the HDRS (Chengappa et al., 2000; Evins et al., 2006) or the Montgomery-Åsberg Depression Rating Scale (MADRS; Montgomery and Åsberg, 1979) (Chengappa et al., 2000; Marsh et al., 2017; Mehrpooya et al., 2018). Naylor and Smith (1981) reported the administration of the HDRS, but results were not presented. Additionally, the same study rated depression according to a global illness scale. Only two of the aforementioned trials have reported significant improvements of nutraceuticals in respect of placebo (Mehrpooya et al., 2018; Naylor and Smith, 1981).

3.4.2. Participants’ characteristics All trials included adult subjects, with mean ages around 40 years old. All had a diagnosis of BD I or II. In four trials (Berk et al., 2012; Ellegaard et al., 2019; Magalhães et al., 2011; Toniolo et al., 2018) participants were depressed, in other two (Applebaum et al., 2007; Scarna et al., 2003) participants were experiencing a manic episode. One trial (Berk et al., 2008) recruited individuals in different phases of BD. 3.4.3. Intervention characteristics In four studies the active treatment was represented by NAC (Berk et al., 2008; Berk et al., 2012; Ellegaard et al., 2019; Magalhães et al., 2011). In two studies, researchers administered amino acid drinks: in particular, in Applebaum et al. (2007) a tryptophan-free amino acid drink was used in addition to standard therapy, while Scarna et al. (2003) used a branched-chain amino acid drink. Finally, in one recent trial (Toniolo et al., 2018) the active treatment was represented by creatine monohydrate (Table 3).

3.3.5. Efficacy on mania Mania was measured in three trials (Behzadi et al., 2009; Evins et al., 2006; Marsh et al., 2017) by means of the YMRS, but significant improvements were found only after the administration of folic acid (Behzadi et al., 2009). One trial (Naylor and Smith, 1981) rated mania also according to the global illness scale, reporting significant differences between the two groups. 339

340

United Kingdom

Naylor and Smith, 1981

Crossover

Parallel

Parallel

Parallel

Parallel

Parallel

Parallel

Design

Manic or depressive psychosis (ICD)

Bipolar I and II (DSM-5)

Bipolar I and II (DSM-IV)

Mania (DSMIV)

Bipolar I and II (DSM-IV)

Bipolar I and II (DSM-IV)

Bipolar I (DSM-IV)

Mania and depression

Depression

Depression

Hypomania, euthymia

Depression

Depression

Mania

Participants characteristics Episode Type of diagnosis (tool)

Not reported

38.5 (18–65)

Not reported (22–30) 44.3 (18–70)

45.5 (18–65)

43

35

Mean age (range)

24 (24, 24)

89 (45, 44)

33 (16, 17)

10 (5, 5)

17 (9, 8)

24 (12,12)

88 (44,44)

N randomized (active treatment, placebo)

23 (23, 23)

69 (36, 33)

25 (12, 13)

5 (3, 2)

15 (8, 7)

22 (12, 10)

84 (41,43)

N completed (active treatment, placebo)

Vitamin C (plus EDTA)

Coenzyme Q10

Vitamin D

Magnesium

Inositol

Inositol

Folic acid

3g

200 mg

5000 IU

375 mg

1–20 g

2–12 g

3 mg

Intervention characteristics Type of Daily dosage nutraceutical

Olanzapine, quetiapine, lithium, sodium valproate, clonazepam, sertraline, citalopram Nitrazepam, chlorpromazine

Lithium, lamotrigine, valproate, carbamazepine, atypical antipsychotics, antidepressants

Verapamil

Lithium, valproate, antidepressants, antipsychotics

Lithium, valproate, carbamazepine, antidepressants, thyroxine

Sodium valproate

Concomitant medication

2 days

8

12

16

6

6

3

Duration (weeks)

Depression GIS + HDRS Not reported Mania GIS +

Depression MADRS = HDRS = Global impression CGI-I = Depression HDRS = Mania YMRS = Global impression CGI = Psychiatric symptoms BPRS + Depression MADRS = Mania YMRS = Anxiety HAM-A = Depression MADRS +

Mania YMRS +

Results Outcomes and Results

Not reported

Epigastric issues, sleep impairments

No serious adverse events

Not reported

Worsening of psychiatric symptoms in some patients

Liver enzyme rising, severe rashes, agranolucytosis. Loose stools, diarrhea

Adverse events

Legend: BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; CGI-I: Clinical Global Impression-Improvement; CGI-S: Clinical Global Impression-Severity; DSM: Diagnostic and Statistical Manual of Mental Disorders; GIS: Global Illness Scale; HAM-A: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; ICD: International Classification of Diseases; MADRS: Montgomery-Åsberg Depression Rating Scale; YMRS: Young Mania Rating Scale; +: significant improvement in the active treatment group compared to placebo; =: no significant differences between the two groups.

Marsh et al., 2017

Iran

United States

Evins et al., 2006

Mehrpooya et al., 2018

United States

Chengappa et al., 2000

United States, Canada United States

Iran

Behzadi et al., 2009

Giannini et al., 2000

Country

Study characteristics Study

Table 2 Effects of micronutrients on symptoms of bipolar disorder.

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Australia, Brazil

Australia

Berk et al., 2008

Berk et al., 2012

Israel

Country

Applebaum et al., 2007

Study characteristics Study

Parallel

Parallel

Parallel

Design

Bipolar I, II, NOS (DSM-IV). Comorbidities: alcohol dependence, substance abuse

Bipolar I and II (DSM IV)

Bipolar I (DSM-IV)

Depression

Depression, mania, mixed

Mania

Participants characteristics Type of diagnosis Episode (tool)

Table 3 Effects of amino acids on symptoms of bipolar disorder.

45.8

45.6

40.7

Mean age (range)

101 (47, 54)

75 (38,37)

23

N randomized (active treatment, placebo)

93 (44, 49)

75(38,37)

17 (9, 8)

N completed (active treatment, placebo)

N-acetyl cysteine

N-acetyl cysteine

Trypthophanfree amino acid drink

2g

2g

102.1 g amino acids without tryptophan, 75 mL Calogen with 325 mL water added

Intevention characteristics Type of Daily dosage nutraceutical

Not reported

Sodium valproate, lithium, carbamazepine, lamotrigine, antipsychotics, antidepressants, benzodiazepines, others

Sodium valproate

Concomitant medication

24

24

1

Duration (weeks)

341

Not reported

Changed energy, headache, heartburn and pain in joints.

Nausea, vomiting

Adverse events

(continued on next page)

Depression HDRS = Mania YMRS + Global impression CGI + Psychiatric symptoms BPRS = Depression MADRS + BDRS + CGI-I-D = CGI-S-D = Mania YMRS + CGI-I-M = CGI-S-M = Global impression CGII-BP = CGI-S-BP + SLICE/LIFE + Functioning GAF + SOFAS + LIFE-RIFT + Quality of life Q-Les-Q + Cognitive tests Digit span, word learning, TMT-A, TMTB, verbal fluency: results not reported Depression MADRS = BDRS = Mania YMRS = Global impression CGI-S = CGI-I = SLICE/LIFE = Functioning GAF = SOFAS =

Results Outcomes and Results

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342

Brazil

Toniolo et al., 2018

Parallel

Parallel

Parallel

Parallel

Design

Bipolar I and II (DSM-IV)

Bipolar I (DSM-IV)

Bipolar I and II (DSM-IV)

Bipolar I and II (DSM-IV)

Depression

Mania

Depression

Depression

Participants characteristics Type of diagnosis Episode (tool)

43.9 (18–59)

41 (19–62)

42.9

43.3 (18–64)

Mean age (range)

27 (17, 18)

25

17 (10, 7)

80 (40, 40)

N randomized (active treatment, placebo)

23 (12,11)

18 (8,10)

17 (10,7)

52 (26, 26)

N completed (active treatment, placebo)

Creatine monohydrate

Branched-chain amino acid (BCAA) drink

N-acetyl cysteine

N-acetyl cysteine

6g

60 g

1g

3g

Intevention characteristics Type of Daily dosage nutraceutical

Antipsychotics, carbamazepine, lithium, benzodiazepines Lithium, anticonvulsants, atypical antipsychotics, antidepressants, benzodiazepines

Lithium, mood stabilizers, atypical antipsychotics, antidepressants, benzodiazepines

Antidepressants, antipsychotics, lithium, mood stabilizers, benzodiazepine, hypnotics

Concomitant medication

6

1

24

20

Duration (weeks)

Depression MADRS = HDRS = Mania YMRS = Global impression CGI = Functioning FAST =

Depression BDRS + MADRS + Mania YMRS = Functioning GAF + Quality of life Q-LES-Q + Global impression CGI + Mania YMRS + BMSRS +

Depression MADRS = MES = Mania YMRS = Functioning GAF = Global impression GAF-S = CGI = Quality of life WHO =

LIFE-RIFT = Quality of life Q-LES-Q =

Results Outcomes and Results

Pruritus, cramps, headache, constipation, diarrhea, limb edema, reflux, somnolence, dizziness, vertigo and abdominal pain

Nausea, sleepiness

Headache, abdominal pain and diarrhea.

Headache, diarrhoea, nausea and dizziness.

Adverse events

Legend: BDRS: Bipolar Depression Rating Scale; BMSRS: Manic-State Rating Scale; BPRS: Brief Psychiatric Rating Scale; CGI: Clinical Global Impression; CGI-I: Clinical Global Impression-Improvement; CGI-S: Clinical Global Impression-Severity; DSM: Diagnostic and Statistical Manual of Mental Disorders; FAST: Functioning Assessment Short Test; GAF: Global Assessment of Functioning; GAF-S: Global Assessment of Symptoms scale; HDRS: Hamilton Depression Rating Scale; LIFE-RIFT: Range of Impaired Functioning Tool; MADRS: Montgomery-Åsberg Depression Rating Scale; MES: Bech-Rafaelsen Melancholia Scale; Q-LES-Q: Quality of Life Enjoyment and Satisfaction Questionnaire; SLICE/LIFE: Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation; SOFAS: Social and Occupational Functioning Assessment Scale; TMT: Trail-making Test; WHO: World Health Organization Well-Being Index; YMRS: Young Mania Rating Scale; +: significant improvement in the active treatment group compared to placebo; =: no significant differences between the two groups.

United Kingdom

Brazil, Australia

Magalhães et al., 2011

Scarna et al., 2003

Denmark

Country

Ellegaard et al., 2019

Study characteristics Study

Table 3 (continued)

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343

Canada

United States

Chouinard et al., 1985

Murphy et al., 2012

Parallel (three arms)

Parallel

Parallel

Parallel (three arms)

Design

Bipolar I (DSM-IVTR)

Bipolar I (DSM III)

Bipolar I and II (DSM-IV)

Bipolar I, II and NOS (DSM-IVTR)

Depression and mania

Mania

Depression

Depression

Participants characteristics Episode Type of diagnosis (tool)

41.7

41.5 (18–65)

36.5 (18–55)

45.5 (19.6–72)

Mean age (range)

45 (15, 15, 15)

24 (12, 12)

40 (20,20)

181 (59 NAC, 61 CT, 61)

N randomized (active treatment, placebo)

Not reported

24 (12,12)

25 (11, 14)

66 (26 CT, 19 NAC, 21)

N completed (active treatment, placebo)

Omega-3, Omega-3 and cytidine

L-tryptophan and nicotinamide

Acetyl-L-carnitine (ALCAR) and αlipoic acid (ALA)

Combination of nutraceuticals (CT), N-acetyl cysteine

2 g, 4 g

Tryptophan (12 g), nicotinamide (4 g)

ALCAR (1–3 g), ALA (600–1800 mg)

CT: several nutrients, NAC 2g

Intevention characteristics Type of Daily dosage nutraceutical

Standard pharmacotherapy

Haloperidol

Citalopram, quetiapine, zolpidem

Mood stabilizers, antipsychotics, antidepressants, benzodiazepines, lithium

Concomitant medication

16

1

12

16

Duration (weeks)

Mania IMPS = Global impression CGI-S = Depression MADRS = Mania YMRS = Functioning GAF =

Depression MADRS = BDRS = Mania YMRS = Anxiety HAM-A = Global impression CGI-S = Functioning SOFAS = LIFE/RIFT = Quality of life Q-LES-Q = Depression MADRS = HDRS = Mania YMRS = Global impression CGI-S =

Results Outcomes and Results

Gastrointestinal distress

Nausea, anorexia, dizziness, drowsiness and headache

Diarrhea, foulsmelling urine, rash, constipation, and dyspepsia,mildly elevated liver function

Mainly gastrointestinal and behavioral

Adverse events

Legend: ALA: α-lipoic acid; ALCAR: Acetyl-L-carnitine; BDRS: Bipolar Depression Rating Scale; CGI-S: Clinical Global Impression-Severity; CT: combination of nutraceuticals treatment; DSM: Diagnostic and Statistical Manual of Mental Disorders; GAF: Global Assessment of Functioning; HAM-A: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; IMPS: Inpatient Multidimensional Psychiatric Scale; LIFE-RIFT: Range of Impaired Functioning Tool; MADRS: Montgomery-Åsberg Depression Rating Scale; NAC: N-acetyl cysteine; Q-LES-Q: Quality of Life Enjoyment and Satisfaction Questionnaire; SLICE/LIFE: Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation; SOFAS: Social and Occupational Functioning Assessment Scale; YMRS: Young Mania Rating Scale; +: significant improvement in the active treatment group compared to placebo; =: no significant differences between the two groups.

United States

Australia

Brennan et al., 2013

Berk et al., 2019

Study characteristics Study Country

Table 4 Effects of combinations of nutraceuticals on symptoms of bipolar disorder.

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(Chouinard et al., 1985) to 181 randomized participants (Berk et al., 2019). Duration varied from one week (Chouinard et al., 1985) to 16 weeks (Berk et al., 2019; Murphy et al., 2012). Data are reported in Table 4.

3.4.4. Efficacy on depression Depression was measured in six out of seven trials, by means of the HDRS (Applebaum et al., 2007; Toniolo et al., 2018), the MADRS (Berk et al., 2008; Berk et al., 2012; Ellegaard et al., 2019; Magalhães et al., 2011; Toniolo et al., 2018) or the Bipolar Depression Rating Scale (BDRS; Berk et al., 2007) (Berk et al., 2008; Berk et al., 2012; Magalhães et al., 2011). Ellegaard et al. (2019) also used the BechRafaelsen Melancholia Scale (MES; Bech and Rafaelsen, 1980). Significant positive effects of NAC on depressive symptoms were found in trials conducted by Berk (Berk et al., 2008) and Magalhães (Magalhães et al., 2011). However, no significant effects on depressive symptoms were found in all the other trials involving the use of amino acids and derivative compounds (Table 3).

3.5.2. Participants’ characteristics All studies included adults. Chouinard et al. (1985) recruited patients in manic phase, Murphy et al. (2012) included mixed samples, with people in both depressive and manic phase; two studies included only depressed subjects (Berk et al., 2019; Brennan et al., 2013). 3.5.3. Intervention characteristics As reported in Table 4, one study tested the effect of α-lipoic acid, in combination with acetyl-L-carnitine (Brennan et al., 2013). Another one (Murphy et al., 2012) was a three-arms RCT, with groups treated with a combination of omega-3 and cytidine, omega-3 alone, or placebo. Also, in Berk et al. (2019) there were three arms of treatment, in which a combination of nutraceuticals, NAC or placebo were administered, respectively. Finally, one trial used L-tryptophan, in combination with nicotinamide (Chouinard et al., 1985).

3.4.5. Efficacy on mania Manic symptoms were evaluated by means of the YMRS in all seven studies. Scarna et al. (2003) also used the Manic-State Rating Scale (BMSRS; Beigel et al., 1971). Three studies (Applebaum et al., 2007; Berk et al., 2008; Scarna et al., 2003) found significant improvements in mania, while the others (Berk et al., 2012; Ellegaard et al., 2019; Magalhães et al., 2011; Toniolo et al., 2018) did not find any significant differences of NAC or creatine monohydrate in respect of placebo.

3.5.4. Effect on depression Berk et al. (2019); Brennan et al. (2013) and Murphy et al. (2012) evaluated depression, by means of MADRS, HDRS, or BDRS, with no significant improvements compared to placebo.

3.4.6. Efficacy on clinical impression, functioning and quality of life As reported in Table 3, two trials found overall significant improvements in the CGI scores in the group of active treatment (Applebaum et al., 2007; Magalhães et al., 2011). Magalhães et al. (2011) also found a significant improvement in functioning, evaluated with GAF, and quality of life, by means of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q; Endicott et al., 1993). In the study conducted by Berk et al. (2008) a significant difference was found between NAC and placebo groups at the CGI-S-BP, but not in the other scales of clinical global impression. However, functioning significantly improved at the GAF, Social and Occupational Functioning Assessment Scale (SOFAS; Morosini et al., 2000) and Range of Impaired Functioning Tool (LIFE-RIFT; Leon et al., 1999). These results were not confirmed by Berk et al. (2012), that adopted the same scales, neither by Ellegaard et al. (2019). Finally, Toniolo et al. (2018) did not find any improvements in clinical impression or in functioning, measured by means of the Functioning Assessment Short Test (FAST; Rosa et al., 2007).

3.5.5. Effect on mania All studies evaluated manic symptoms, with the YMRS (Berk et al., 2019; Brennan et al., 2013; Murphy et al., 2012), or the Inpatient Multidimensional Psychiatric Scale (IMPS; Lorr, 1962) (Chouinard et al., 1985), with no differences between the two groups (Table 4). 3.5.6. Effect on clinical global impression, functioning, quality of life and anxiety No significant differences in clinical global impression, measured by Brennan et al. (2013) and Chouinard et al. (1985), neither in functioning, measured by Murphy et al. (2012) were found. CGI and GAF were used to measure these outcomes. Berk et al. (2019) measured several domains, such as global impression (CGI), functioning (SOFAS and LIFE/RIFT), quality of life (Q-LES-Q) and anxiety (HAM-A; Maier et al., 1988), but none of these outcomes showed statistically significant differences between either NAC or the combination of nutraceuticals, and placebo.

3.4.7. Adverse events All studies reported no significant differences in adverse events between the active treatment and placebo groups. Side effects were mainly related to gastrointestinal symptoms, such as diarrhea or vomiting.

3.5.7. Adverse events Adverse events were mainly related to gastrointestinal symptomatology.

3.4.8. Risk of bias According to the Cochrane's tool, five studies had adequate random sequence generation and allocation concealment, while two trials did not provide sufficient information, and were thus judged as unclear in both domains (Applebaum et al., 2007; Magalhães et al., 2011). Allocation concealment was unclear also in Ellegaard et al. (2019). All studies had blinding of participants, personnel and outcome assessors. Risk of attrition bias and selective reporting were unclear only in one of the included studies (Applebaum et al., 2007) (Fig. 2c).

3.5.8. Risk of bias Randomization and allocation concealment were unclear in two studies (Chouinard et al., 1985; Murphy et al., 2012), while one trial (Brennan et al., 2013) was judged at low risk of bias. All other domains were considered at low risk of bias, apart from attrition in the study by Brennan et al. (2013), that we rated as unclear (Fig. 2d). 3.6. Probiotics

3.5. Combination of different types of nutraceuticals 3.6.1. Study, participants, and intervention characteristics We found only one 24-week parallel RCT (Dickerson et al., 2018) evaluating the effectiveness of probiotics, specifically Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12 in adults (mean age 35.6) with BD type I or schizoaffective disorder, bipolar type (manic or mixed state), diagnosed according to DSM-IV-TR criteria (Table 5).

3.5.1. Study characteristics We finally included four studies evaluating the effect of combinations of nutraceuticals on symptoms of BD. All studies were parallel RCTs. Two were conducted in the United States (Brennan et al., 2013; Murphy et al., 2012), one in Canada (Chouinard et al., 1985), and one in Australia (Berk et al., 2019). Sample sizes ranged from 24 344

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Legend: BPRS: Brief Psychiatric Rating Scale; DSM: Diagnostic and Statistical Manual of Mental Disorders; MADRS: Montgomery-Åsberg Depression Rating Scale; YMRS: Young Mania Rating Scale; +: significant improvement in the active treatment group compared to placebo; =: no significant differences between the two groups.

Cardiovascular, gastrointestinal, neurological symptoms Depression MADRS = Mania YMRS = Psychiatric symptoms BPRS = N of rehospitalizations + 24 Typical and atypical ntipsycothics, mood stabilizers, lithium, antidepressants Dickerson et al., 2018

United States

Parallel

Bipolar I, II or schizoaffective disorder, manic type (DSM-IV)

Depression, mania

35.6 (18–65)

66 (33,33)

52 (26, 26)

Probiotics (lactobacillus rhamnosus strain GG and bifidobacterium animalis subsp. lactis strain Bb12)

Lactobacillus GG and Bifidobacterium lactis strain Bb12 (>108 colonyforming units)

Duration (weeks) Participants characteristics Type of diagnosis Episode (tool) Design Study characteristics Study Country

Table 5 Effects of probiotics on symptoms of bipolar disorder.

Mean age (range)

N randomized (active treatment, placebo)

N compeleted (active treatment, placebo)

Intervention characteristics Type of Dosage nutraceutical

Concomitant medication

Results Outcomes nad Results

Adverse events

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3.6.2. Efficacy on depression Depression was measured with MADRS, and no significant improvements were found in both groups. Additionally, there were no significant differences between the placebo and the probiotic group at any study visit. 3.6.3. Efficacy on mania Manic symptoms were evaluated through the YMRS; there were overall significant improvements for the sample as a whole in the YMRS scales, but no significant differences were found between the two groups. 3.6.4. Efficacy on general psychiatric symptoms The authors found overall significant improvements in the BPRS scores, but no differences between the two groups. The number of rehospitalizations was significantly lower in the treatment group than in the placebo group. 3.6.5. Adverse events Dickerson et al. (2018) reported no significant differences in somatic adverse events between the probiotic and the placebo group. In general, study medication was well-tolerated and there were no withdrawals due to complaints about the study medication. 3.6.6. Risk of bias According to the Cochrane's tool (Higgins et al., 2011), the study was found having an overall low risk of bias (Fig. 2e). 4. Discussion Nutraceuticals are a group of non-psychotropic compounds of growing interest in medical research, and particularly in psychiatry (Jacka, 2017). Since pharmacological treatments are frequently burdened by side effects, the use of nutraceuticals may consent a reduction of drug posology, improving patients’ compliance (Santini et al., 2017). For this reason, we aimed to provide an up-to-date overview of the effectiveness of different types of nutraceuticals in BD, one of the most impairing psychiatric diseases (Rowland and Marwaha, 2018). Fatty acids have demonstrated a positive effect on symptoms of several neuropsychiatric conditions (Politi et al., 2013). Of note, several papers have highlighted their efficacy in mood disorders (Grosso et al., 2014; Montgomery and Richardson, 2008). Our systematic review confirmed that omega-3 fatty acids may be useful in the treatment of depressive symptoms of BD. Biological mechanisms of the antidepressant effects of omega-3 are mostly unclear (Montgomery and Richardson, 2008). Nevertheless, some possible explanations have been postulated. First, a reduction of fatty acids was found in the membrane of erythrocytes of manic patients in respect of healthy controls (Chiu et al., 2003), thus supporting a role of fatty acids deficiency in the etiology of BD. Second, omega-3 fatty acids can influence a wide range of neurotransmitters, including dopamine, serotonin and noradrenaline, either directly or via their effects on membrane fluidity (Montgomery and Richardson, 2008). Additionally, their anti-depressant effect could be due to the anti-inflammatory properties. Omega-3, in fact, attenuate the production of inflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6) or tumor necrosis factor-α (TNF-α), that can produce clinical symptoms of depression (Maes et al., 2009). Finally, omega-3 have a neurotrophic effect, increasing the production of brain derived neurotrophic factor (BDNF) (Wu et al., 2004), a neurotrophin with antidepressant properties (Hoshaw et al., 2005). Conversely, according to our findings, the utility of fatty acids in manic phase of BD is still unclear. In fact, only one study (Shakeri et al., 2016) reported significant improvements at the YMRS in the omega-3 group. However, it is worth mentioning that in this paper no direct comparisons between the active treatment and control group were performed. We could hypothesize that, given the 345

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for acetyl-L-carnitine, that previous reports have associated with an improvement of mood disturbances (Martinotti et al., 2011). However, Brennan et al. (2013), that tested acetyl-L-carnitine in association with α-lipoic acid, did not find significant ameliorations. Also, it has been recently shown that NAC may modulate the redox status of gut microbiota, as well as its composition (Xu et al., 2014; Zheng et al., 2019). Alterations of gut microbiota has in turn been linked to the onset of mood disorders (Dickerson et al., 2017; Mangiola et al., 2016). NAC could thus be classified among the so-called “psychobiotics”, a group of non-psychotropic substances which have shown a potential utility in the treatment of mental disorders (Misra and Mohanty, 2017). Recently, clinical research has directed several efforts to the study of gut microbiota alterations in psychiatric diseases. In line with this trend, Dickerson and colleagues (Dickerson et al., 2018) tested probiotics in BD. Results were not totally satisfying. In fact, despite depressive and manic symptoms significantly improved after the treatment with probiotics, no significant differences with the placebo group could be detected. However, the number of rehospitalizations was significantly reduced in patients treated with probiotics, suggesting a potential usefulness of these supplements. Unfortunately, although initially planned, we were unable to perform a meta-analysis, since included trials were too heterogeneous from several points of view. First, patients were in different phases of BD (mania, depression or euthymia). Second, several types of nutraceuticals, even if belonging to the same a priori determined category, were used. Since nutraceutical may act through several biological mechanisms on the different symptoms, we did not consider methodologically appropriate to perform a quantitative data synthesis. Despite this important limitation, we believe that our review has been conducted following a strong methodological procedure, in respect of PRISMA guidelines (Moher et al., 2009), presenting results in a clear manner and outlining the main features of the included studies. We also limited the inclusion only to placebo-controlled RCTs. Inclusion criteria might appear too restrictive in respect of previous systematic reviews (Sarris et al., 2011), but allow comparing nutraceuticals with a nonactive treatment, avoiding potential biases. This restriction may have excluded studies regarding substances which have demonstrated promising results in the treatment of mood disorders, such as saffron (Shafiee et al., 2018) or curcumin (Ng et al., 2017). Finally, we have not included nutraceuticals for sleep promotion (e.g. melatonin), because they are generally used to manage comorbid sleep disorders and not core symptoms of BD. Apart from the general limitations of our review, it is important to underline also potential caveats of the single papers. Placebo-controlled trials are usually conducted with a strong methodology, as evidenced also by the risk of bias assessment. However, several of the included studies randomized small sample sizes, potentially being underpowered to detect any significant difference. Also, duration of trials might not be adequate to see clinically relevant improvements. Additionally, participants were often experiencing different mood episodes (i.e. mania and depression), thus hampering the generalizability of results. Another limitation might be related to the lack of clear information about the dietary regimens followed by recruited patients, as well as the level of nutrients at baseline, which could potentially modify the efficacy of nutraceuticals. Additionally, standard pharmacological therapy was different across studies and participants. Finally, even if some papers emphasized a significant improvement in the active treatment group, no significant differences with placebo could be actually detected. Of note, in some studies no between-group analyses were performed. Nevertheless, it is important to underline that the general quality of the trials largely improved over the years. In conclusion, our systematic review revealed inconsistent results about the effectiveness of nutraceuticals on symptoms of BD. Some of them seem to be potentially useful, but positive results often rely on single or few studies. However, it is worth mentioning that nutraceuticals appeared generally safe and free of important side effects.

aforementioned antidepressant effects of omega-3 fatty acids, a positive effect also on mania is unlikely. However, it has been shown that ingestion of omega-3 fatty acids cause a reduction of some signal transduction pathways. Therefore, omega-3 may act as mood stabilizers in BD, a condition in which there is an overactivity of signal transduction (Sperling et al., 1993). Concerning micronutrients (i.e. essential elements required by the organism in small quantities, such as vitamins and minerals), only one study, in which acid folic was administered (Behzadi et al., 2009), showed promising effects on manic symptoms. Biological mechanisms underlying this improvement are mainly unknown. One possible justification is related to the deficits of acid folic and vitamin B12 found in patients with BD (Ozbek et al., 2008). Folic acid is important for the catabolism of homocysteine, a protein that interacts with brain glutamate receptors. These receptors, if hyperactivated, could favor the onset of BD (Mattson and Shea, 2003). Conversely, coenzime Q10, an endogenous lipid-soluble substance with antioxidant, anti-inflammatory, and mitochondrial modulatory properties, seemed to decrease depressive symptoms in a group of patients with BD (Mehrpooya et al., 2018). This is in line with the hypothesis that mitochondrial dysfunctions, inflammatory alterations, and oxidative stress might play a role in the etiopathogenesis of BD (Mehrpooya et al., 2018). Moreover, in one trial, magnesium oxide improved psychiatric symptoms, increasing the verapamil maintenance therapy of a group of patients who had suffered from a manic episode (Giannini et al., 2000). This result could be related not only to the lower concentration of magnesium found in subjects with BD by some researchers (Nechifor et al., 2006), but also to its calcium-regulatory actions, with a reduction of dopaminergic and adrenergic release (Giannini et al., 2000). Finally, vitamin C seemed effective in the crossover trial published by Naylor and Smith (1981). However, this trial is quite old and, as shown by the risk of bias assessments, presents several caveats. Therefore, results need to be cautiously interpreted. Two trials comparing the effects of amino acid drinks to placebo (Applebaum et al., 2007; Scarna et al., 2003) found significant effects on mania. In the first case (Applebaum et al., 2007), it is likely that the administration of a tryptophan-free drink may have caused a reduction in serotonin levels without directly affecting other neurotransmitters (Young et al., 1989). In fact, it has been suggested that serotoninergic hyperactivity plays a role in manic states, in contrast with its presumed hypoactivity in depression (Shiah and Yatham, 2000). A similar mechanism has been hypothesized by Scarna et al. (2003), that administered a tyrosine-free amino acid drink, composed only by leucine, isoleucine and valine. These amino acids compete with phenylalanine and tyrosine for brain entry, producing an attenuation of dopamine neurotransmission (Gijsman et al., 2002). However, it is important to underline that these compounds cannot be administered for a long period, since they may cause potentially relevant nutritional deficiencies; in fact, both trials had a duration of one week. According to our systematic review, NAC showed contrasting effects. Some trials reported beneficial effects on depressive symptoms, as well as on global functioning and quality of life of patients with BD (Berk et al., 2008; Magalhães et al., 2011). However, these promising results were not confirmed by other recent studies (Berk et al., 2012; Berk et al., 2019; Ellegaard et al., 2019). On the contrary, mania significantly improved only in one trial (Berk et al., 2008). Reasons for the anti-depressant properties of NAC may again rely on its anti-inflammatory activity (Dean et al., 2009), mainly related to its capacity to replenish brain levels of glutathione, a major antioxidant. Additionally, NAC seems to directly act on glutamatergic transmission (Dean et al., 2011). For this reason, some authors recently hypothesized that NAC might play a role in the treatment of addictions, such as cocaine dependence or gambling (Pettorruso et al., 2014), which could be comorbid conditions of BD (Di Nicola et al., 2014). In fact, a portion of the patients recrutited by Berk et al., 2012 had a comorbid substance or alcohol dependence. Antioxidant mechanisms have been reported also 346

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This may explain the reason why nutraceuticals are frequently prescribed by clinicians to populations at risk, such as older people, pregnant women or patients with alcohol dependence. Nevertheless, since mechanisms of action remain largely unclear, the use of nutraceuticals should be suggested with cautiousness. In fact, recent authors have shown potential interactions with psychotropic medications (Ronis et al., 2018), as well as changes in the composition of gut microbiota (Catinean et al., 2018). More clinical trials are needed to better elucidate the role of nutraceuticals in treating core symptoms of BD. BD is characterized by different phases, that range from severe depression to hypomania or mania. Nutraceuticals may act according to distinct, sometimes opposite, mechanisms, in each mood episode. Therefore, it is important for future researchers to better characterize and, possibly, harmonize the samples recruited in trials examining the role of nutraceuticals in BD. Additionally, all concomitant conditions potentially influencing the response to treatment (i.e., baseline nutrient levels, dietary regimen) should be clearly explained. Finally, the role of promising substances not included in this review (e.g. saffron, curcumin, etc.) deserves to be tested by researchers in future investigations.

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Conflict of interest disclosure All authors declare no conflict of interest. Contributions L.F. conceived the study, wrote the protocol, participated in data extraction, and wrote the manuscript. T.S., A.V., V.M. and F.P. managed the literature searches, performed data extraction and participated in drafting the manuscript with critical contributions. R.F., M.S.S., and E.A. supervised the study and critically contributed to the draft of the manuscript. All authors have read and approved the final manuscript. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgments None. Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jad.2019.04.039. References Abed, S.N., Younes, F.A., Surchi, H.S., Deb, P.K., 2018. Herbal medication and nutraceuticals for the management of anxiety and depression. Curr. Psychopharmacol. 7, 129–148. Applebaum, J., Bersudsky, Y., Klein, E., 2007. Rapid tryptophan depletion as a treatment for acute mania: a double‐blind, pilot‐controlled study. Bipolar Disord. 9, 884–887. American Psychiatric Association, 2013. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). American Psychiatric Pub. Bech, P., Rafaelsen, O.J, 1980. The use of rating scales exemplified by a comparison of the Hamilton and the Bech‐Rafaelsen Melancholia Scale. Acta Psychiatr. Scand. 62, 128–132. Behzadi, A., Omrani, Z., Chalian, M., Asadi, S., Ghadiri, M., 2009. Folic acid efficacy as an alternative drug added to sodium valproate in the treatment of acute phase of mania in bipolar disorder: a double‐blind randomized controlled trial. Acta Psychiatr. Scand. 120, 441–445. Beigel, A., Murphy, D.L., Bunney, W.E., 1971. The Manic-State Rating Scale: scale construction, reliability, and validity. Arch. Gen. Psychiatry. 25, 256–262. Belzeaux, R., Boyer, L., Féron, F., Leboyer, M., Fond, G., 2015. Mood disorders are associated with a more severe hypovitaminosis D than schizophrenia. Psychiatry Res. 229, 613–616. Berk, M., Copolov, D.L., Dean, O., Lu, K., Jeavons, S., Schapkaitz, I., Anderson-Hunt, M., Bush, A.I., 2008. N-acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol. Psychiatry 64, 468–475.

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