Re: schizophrenia 치료 보충제 Nutraceuticals ...DHA, EPA(오메가 3) 2024

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Nutraceuticals in Psychiatric Disorders: A Systematic Review

by 

Paola Bozzatello

 *,

Roberta Novelli

,

Cristiana Montemagni

Department of Neuroscience, University of Turin, Via Cherasco 15, 10126 Turin, Italy

*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2024, 25(9), 4824; https://doi.org/10.3390/ijms25094824

Submission received: 4 April 2024 / Revised: 23 April 2024 / Accepted: 25 April 2024 / Published: 28 April 2024

(This article belongs to the Special Issue Investigation of Natural Products as Sources of Bioactive Molecules)

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Abstract

Correct nutrition and diet are directly correlated with mental health, functions of the immune system, and gut microbiota composition. Diets with a high content of some nutrients, such as fibers, phytochemicals, and short-chain fatty acids (omega-3 fatty acids), seem to have an anti-inflammatory and protective action on the nervous system. Among nutraceuticals, supplementation of probiotics and omega-3 fatty acids plays a role in improving symptoms of several mental disorders. In this review, we collect data on the efficacy of nutraceuticals in patients with schizophrenia, autism spectrum disorders, major depression, bipolar disorder, and personality disorders. This narrative review aims to provide an overview of recent evidence obtained on this topic, pointing out the direction for future research.

초록

올바른 영양 섭취와 식이요법은

정신 건강, 면역 체계 기능, 장내 미생물군 구성과 직접적인 상관관계가 있다.

섬유질, 식물성 화학물질, 단쇄 지방산(오메가-3 지방산)과 같은 특정 영양소가 풍부한 식단은

신경계에 항염증 및 보호 작용을 하는 것으로 보인다.

기능성 식품 중 프로바이오틱스와 오메가-3 지방산 보충은

여러 정신 장애 증상 개선에 역할을 한다.

본 리뷰에서는

정신분열증, 자폐 스펙트럼 장애, 주요 우울증, 양극성 장애, 인격 장애 환자에서

기능성 식품의 효능에 관한 데이터를 수집한다.

이 서술적 리뷰는 해당 주제에 관한 최근 증거를 종합하고

향후 연구 방향을 제시하는 것을 목표로 한다.

Keywords: 

nutraceuticals; omega-3 fatty acids; probiotics; psychiatric disorders

1. Introduction

Over the past decades, growing evidence has been obtained that proper nutrition with high intakes of nutrients such as fibers, phytochemicals, and short-chain fatty acids (omega-3 fatty acids) is correlated with mental health and prevention of neurodevelopmental disorders [1,2,3,4,5].

The effects of omega-3 fatty acids on inflammatory processes, the cardiovascular system, and the nervous system are recognized by many studies [1,3,4,6]. Polyunsaturated omega-3 fatty acids are important components of phospholipids and cholesterol esters of the neuronal cell membrane, especially of dendritic and synaptic membranes. In the brain, these agents modulate brain cell signaling, involving dopaminergic and serotonergic pathways [2,7,8]. They produce modifications of the phospholipid fatty acid composition of the synaptic membrane and modulate the cascade of second messengers [9,10,11]. In particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are significant regulating factors of neurogenesis, cell survival, and neurotransmission [3,12].

1. 서론

지난 수십 년간

섬유질, 식물성 화학물질, 단쇄 지방산(오메가-3 지방산)과 같은

영양소를 풍부하게 섭취하는 적절한 영양이

정신 건강 및 신경발달 장애 예방과 관련이 있다는 증거가 점점 더 많이 확보되었습니다[1,2,3,4,5].

오메가-3 지방산이

염증 과정, 심혈관계 및 신경계에 미치는 영향은 다수의 연구를 통해 입증되었다[1,3,4,6].

다중불포화 오메가-3 지방산은

신경 세포막, 특히 수상돌기 및 시냅스 막의 인지질과 콜레스테롤 에스테르의 중요한 구성 성분이다.

뇌에서 이 물질들은

도파민 및 세로토닌 경로를 포함한 뇌 세포 신호 전달을 조절한다[2,7,8].

이들은 시냅스 막의 인지질 지방산 구성을 변화시키고

2차 전달물질의 연쇄 반응을 조절한다[9,10,11].

특히

에이코사펜타엔산(EPA)과 도코사헥사엔산(DHA)은

신경 발생, 세포 생존 및 신경 전달의 중요한 조절 인자이다[3,12].

Also, the human gut microbiota, through the secretion of short-chain fatty acids, which can modulate tryptophan availability and vagal activation, can alter inflammatory signaling in the brain [13]. Therefore, changes in the microbiome may affect cognitive ability and behavior [13,14]. A strong relationship between microbiome status and neurocognitive states has been reported [15]. Furthermore, changes in the activity of different brain regions in response to changes in the microbiome suggest that the human microbiome and associated products are important determinants of neuronal coordination [16].

Several studies have shown that neuropsychiatric and neurodegenerative disorders such as major depressive disorder, bipolar disorder, Parkinson’s disease, Alzheimer’s disease, functional disorders, and autoimmune disorders such as multiple sclerosis are linked to neuroinflammation and that their onset and regulation depend on certain physical factors, including the microbiome [13,17,18].

또한 인간 장내 미생물군은

트립토판 가용성과 미주신경 활성화를 조절할 수 있는 단쇄 지방산의 분비를 통해

뇌의 염증 신호 전달을 변화시킬 수 있다[13].

따라서

미생물군집의 변화는

인지 능력과 행동에 영향을 미칠 수 있다[13,14].

미생물군집 상태와

신경인지 상태 간 강한 연관성이 보고된 바 있다[15].

더욱이 미생물군집 변화에 반응하여 다양한 뇌 영역의 활동이 변화한다는 점은

인간 미생물군집 및 관련 산물이 신경 세포 간 조정의 중요한 결정 요인임을 시사한다[16].

여러 연구에 따르면

주요 우울 장애, 양극성 장애, 파킨슨병, 알츠하이머병과 같은

신경정신과적 및 신경퇴행성 장애,

기능성 장애,

다발성 경화증과 같은 자가면역 장애는 신경염증과 연관되어 있으며,

그 발병과 조절은 미생물군집을 포함한 특정 물리적 요인에 의존한다[13,17,18].

Based on these findings, omega-3 was also studied as a potential treatment for several psychiatric disorders such as schizophrenia, major depression, bipolar disorder, autism spectrum disorders, and personality disorders [12,19,20,21,22,23,24]. Concerning the effects of nutraceuticals on psychiatric symptoms and/or disorders, data are still limited. Existing evidence pointed out that supplementation with omega-3 fatty acids provides benefits in the main psychiatric symptom dimensions, particularly in affective symptoms, impulsivity, and harmful behaviors [25,26,27].

This narrative review aims to provide an updated account of the available evidence of the impact of omega-3 fatty acids and other nutraceuticals on psychopathology in patients with schizophrenia, autism spectrum disorder, major depression, bipolar disorder, and personality disorders. The objective is to establish whether data collected in trials of omega-3 fatty acids and nutraceuticals in the treatment of psychiatric disorders support their indications in treating patients with specific diagnoses.

이러한 연구 결과를 바탕으로 오메가-3는

정신분열증, 주요 우울증, 양극성 장애, 자폐 스펙트럼 장애, 인격 장애 등

여러 정신 질환의 잠재적 치료제로도 연구되었다[12,19,20,21,22,23,24].

영양 보충제가

정신 증상 및/또는 장애에 미치는 영향에 관한 데이터는 여전히 제한적이다.

기존 증거는

오메가-3 지방산 보충이 주요 정신 증상 차원,

특히 정서적 증상, 충동성 및 유해 행동에서 이점을 제공한다고 지적했다[25,26,27].

본 서술적 문헌고찰은

오메가-3 지방산 및 기타 기능성 식품이 정신분열증, 자폐 스펙트럼 장애, 주요 우울증, 양극성 장애, 성격 장애 환자의 정신병리학에 미치는 영향에 관한 최신 증거를 종합적으로 제시하는 것을 목표로 한다.

정신질환 치료를 위한 오메가-3 지방산 및 기능성 식품 임상시험에서 수집된 데이터가 특정 진단을 받은 환자 치료에 대한 적응증을 뒷받침하는지 규명하는 것이 목적이다.

2. Methods

In January 2024, an electronic search was performed on PubMed on the role of nutraceuticals, probiotics, and omega-3 fatty acid supplementation in the treatment of psychiatric disorders such as personality disorders, schizophrenia, bipolar disorder, major depression, and autism spectrum disorders using the following search string in PubMed (“Gastrointestinal Microbiome”[MeSH Terms] OR microbiota[title] OR microbiome[title] OR ((“Gastrointestinal Tract”[MeSH] OR gastrointestin*[title] OR gastro-intest*[title] OR intestin*[title] OR bowel[title] OR colon*[title] OR enter*[title] OR gut[title] OR gastri*[title]) AND (microb*[title] OR flora[title] OR bacteri*[title] OR microflora[title] OR microorganism*[title] OR micro-organism*[title]))) AND (“Fatty Acids, Omega-3”[MeSH] OR Omega-3[title] OR n-3[title] OR n3[title] OR “Dietary Supplements”[MeSH] OR “dietary supplement*”[title] OR nutraceutic*[title] OR nutriceutic*[title] OR neutraceutic*[title] OR “Dietary Fiber”[MeSH] OR fiber*[title] OR prebiotic*[title] OR probiot*[title] OR synbiot*[title] OR “Vitamins”[MeSH] OR “Vitamins”[Pharmacological Action] OR “Provitamins”[Pharmacological Action] OR vitamin*[title] OR provitamin*[title]) AND (“Depression”[MeSH Terms] OR depress*[title] OR “Bipolar Disorder”[MeSH Terms] OR bipolar*[title] OR psychos*[title] OR psychot*[title] OR “Personality Disorders”[MeSH Terms] OR “personality disorder*”[title] OR borderline[title] OR psychopath*[title] OR psycho-path*[title] OR “Schizophrenia Spectrum and Other Psychotic Disorders”[MeSH] OR schizo*[title] OR parano*[title] OR “Autism Spectrum Disorder”[MeSH Terms] OR autis*[title] OR Asperger*[title] OR “mental disorder*”[title] OR “mental illness*”[title] OR “mental health”[title] OR psychiatr*[title] OR “paranoid personality disorder”[MeSH] OR “antisocial personality disorder”[MeSH] OR “istrionic personality disorder”[MeSH] OR “avoidant personality disorder”[MeSH] OR “narcissist personality disorder”[MeSH] OR “obsessive-compulsive personality disorder”[MeSH] OR “schizoid personality disorder”[MeSH] OR “schizotypal personality disorder”[MeSH] OR “borderline personality disorder”[MeSH]) AND (2014:3000/12/12[pdat]). The search string is displayed in the Figure 1.

2. 방법

2024년 1월, PubMed에서 성격 장애, 조현병, 양극성 장애, 주요 우울증, 자폐 스펙트럼 장애와 같은 정신 질환 치료에서 기능성 식품, 프로바이오틱스 및 오메가-3 지방산 보충제의 역할에 대해 전자 검색을 수행했습니다.

PubMed에서 다음과 같은 검색 문자열을 사용했습니다

(“위장관 미생물군집” [MeSH 용어] OR microbiota[제목] OR microbiome[제목] OR ((“Gastrointestinal Tract”[MeSH] OR gastrointestin*[제목] OR gastro-intest*[제목] OR intestin*[제목] OR bowel[제목] OR colon*[제목] OR enter*[제목] OR gut[제목] OR gastri*[제목]) AND (microb* [title] OR flora[title] OR bacteri*[title] OR microflora[title] OR microorganism*[title] OR micro-organism*[title]))) AND

(“Fatty Acids, Omega-3”[MeSH] OR Omega-3[title] OR n-3[title] OR n3[title] OR

“Dietary Supplements”[MeSH] OR “dietary supplement*” [제목] 또는

nutraceutic*[제목] 또는 nutriceutic*[제목] 또는 neutraceutic*[제목] 또는

“식이섬유”[MeSH] 또는 fiber*[제목] 또는

prebiotic*[제목] 또는 probiot*[제목] 또는 synbiot*[제목] 또는

“비타민”[MeSH] 또는 “Vitamins” [약리작용] 또는 “전비타민” [약리학적 작용] OR 비타민*[제목] OR 프로비타민*[제목]) AND

(“우울증”[MeSH 용어] OR 우울*[제목] OR

“양극성 장애”[MeSH 용어] OR 양극성*[제목] OR

정신병*[제목] OR 정신병적*[제목] OR

“성격 장애”[MeSH 용어] OR “성격 장애*” [제목] 또는 경계성[제목] 또는 정신병자*[제목] 또는

정신병적*[제목] 또는 “정신분열증 스펙트럼 및 기타 정신병적 장애”[MeSH] 또는

정신분열증*[제목] 또는 편집증*[제목] 또는

“자폐 스펙트럼 장애”[MeSH 용어] 또는 자폐증*[제목] 또는

아스퍼거*[제목] 또는 “정신 장애*” [제목] 또는 “정신 질환*”[제목] 또는

“정신 건강”[제목] 또는 정신의학*[제목] 또는

“편집성 인격 장애”[MeSH] 또는 “반사회적 인격 장애”[MeSH] 또는 “연극성 인격 장애”[MeSH] 또는

“회피성 인격 장애”[MeSH] 또는 “자기애성 인격 장애”[MeSH] OR “강박성 인격 장애”[MeSH] OR

“분열형 인격 장애”[MeSH] OR “분열형 인격 장애”[MeSH] OR

“경계선 인격 장애”[MeSH]) AND (2014:3000/12/12[pdat]). 검색 문자열은 그림 1에 표시되어 있습니다.

Figure 1. Search string on PubMed.

We included the following types of publications: randomized controlled trials (RCTs), follow-up studies, open-label trials, proof-of-concept studies, posthoc subgroup analyses, naturalistic follow-up studies, pilot studies series, case studies, narrative reviews, systematic reviews, meta-analysis from January 2014 to February 2024. We have excluded observational studies, longitudinal studies, prospective studies, and letters to the author. Overlapping studies were also excluded.

Eligibility status for articles was determined in the following way: (1) all studies were screened based on the title and abstract and (2) papers that passed the initial screening were reviewed based on a careful examination of the full manuscript content. The review considered only articles written in English.

To make the review as comprehensive as possible, all articles with a cohort size between 1 and 377 patients were selected; patients in whom the psychiatric disorder had already been diagnosed and subjects at risk were examined; the observation period was between 3 and 260 weeks. No age limits were set. Studies were examined in which a single agent was eval‎uated against a placebo and studies in which two or more compounds were compared with each other, with or without the combination of psychiatric medications. No ethnicity was excluded. Details of the studies are reported in the tables [Table 1, Table 2, Table 3, Table 4 and Table 5].

그림 1. PubMed 검색 문자열.

2014년 1월부터 2024년 2월까지의 무작위 대조 시험(RCT), 추적 연구, 공개 시험, 개념 증명 연구, 사후 하위군 분석, 자연주의적 추적 연구, 파일럿 연구 시리즈, 사례 연구, 서술적 리뷰, 체계적 리뷰, 메타분석 등 다양한 유형의 출판물을 포함했습니다. 관찰 연구, 종단 연구, 전향적 연구 및 저자에게 보내는 서한은 제외하였습니다. 중복 연구도 제외하였습니다.

논문의 적격 여부는 다음과 같은 방식으로 결정하였습니다:

(1) 모든 연구를 제목과 초록을 기준으로 선별하고

(2) 초기 선별을 통과한 논문은 전체 원고 내용을 면밀히 검토하여 평가하였습니다.

검토는 영어로 작성된 논문만을 대상으로 하였습니다.

검토의 포괄성을 극대화하기 위해,

코호트 규모가 1명에서 377명 사이인 모든 논문을 선정했습니다.

정신 질환이 이미 진단된 환자와 위험군 대상자를 모두 포함했으며,

관찰 기간은 3주에서 260주 사이였습니다.

연령 제한은 설정하지 않았습니다.

단일 약제를 위약과 비교 평가한 연구와 두 가지 이상의 화합물을 서로 비교한 연구(정신과 약물 병용 여부와 무관하게)를 검토했습니다. 특정 인종을 배제하지 않았습니다. 연구 세부 사항은 표 [표 1, 표 2, 표 3, 표 4 및 표 5]에 보고되어 있습니다.

Table 1. Schizophrenia.

Table 2. Autism Spectrum Disorder.

Autism Spectrum DisorderStudyStudy DesignDrugs and DoseCohortTreatmentDurationResults

Bent et al., 2014 [58]	Randomized, controlled trial	1.3 g/day of omega-3 (and 1.1 g of EPA+ DHA)	57 children (5 to 8 years)	6 weeks	↓ hyperactivity
Voigt et al., 2014 [59]	Randomized, double-blind, placebo-controlled trial	0.2 g/day DHA	48 children (3 to 10 years)	26 weeks	No differences
Mankad et al., 2015 [60]	Randomized, placebo-controlled trial	0.75–1.5 g/day EPA + DHA	38 children (2 to 5 years)	26 weeks	No differences
Ooi et al., 2015 [61]	Open label trial	192 mg/day EPA + 840 mg/day DHA	41 patients (7 to 18 years)	12 weeks	Improve SRS-2 ↓ Attention Problems Syndrome Scales of CBCL
Tomova et al., 2015 [62]	Pilot study	3 capsules of probiotics (Children Dophilus®: 3 stumps Lactobacilli 60% + 2 stumps Bifidumbacteria 25% + 1 stump Streptococci 15%)	29 children (10 ASD children, their 9 non-ASD siblings, 10 non-ASD children) (2 to 17 years)	16 weeks	↓ Bacteroidetes/Firmicutes ratio Increase of Lactobacillus spp.
Grossi et al., 2016 [63]	Case study	9 × 10⁹ CFU/day Bifidobacteria + 8 × 1010 CFU/day Lactobacilli + 20 × 1010 CFU/day Streptococci	A 12-year-old child	4 weeks	↓ GI symptoms ↓ ASD symptoms ↓ ADOS-2 score
Sheppard et al., 2017 [64]	Pilot randomized, controlled trial	338 mg EPA + 225 mg DHA + 83 mg GLA + 306 mg Omega 9	31 children (18–38 months of age born at ≤29 weeks of gestation)	12 weeks	↓ early language development in children at risk for ASD
Dae-Wook Kang et al., 2017 [65]	Open-label study	MTT treatment protocol (antibiotic + bowel cleanse + FMT)	38 children (7 to 17 years)	18 weeks (8 weeks follow up)	↓ GI symptoms ↓ behavioral ASD symptoms
Parellada et al., 2017 [66]	Randomized, crossover, placebo-controlled trial	962 mg/day omega-3 for children or 1155 mg/day omega-3 for adolescents	68 patients (5 to 17 years)	8 weeks	No differences
Keim et al., 2018 [67]	Randomized, double-blind, placebo-controlled trial	338 mg/day EPA + 225 mg/day DHA + 83 mg/day GLA	31 patients (18–38 months of age who were born at ≤29 weeks of gestation)	12 weeks	↓ ASD symptoms
Mazahery et al., 2019 [68]	Randomized, controlled trial	2000 UI/day Vit. D or 722 mg/day DHA or 2000 UI/day vit. D + 722 mg/day DHA	117 (2.5 to 8 years)	52 weeks	Vit. D and omega-3: ↓ irritability vit. D: ↓ hyperactivity
Liu et al., 2019 [69]	Randomized, double-blind, placebo-controlled Trial	3 × 1010 CFU/capsule/day (L. plantarum PS128)	80 (7 to 15 years)	4 weeks	↓ disruptive and rule-breaking behaviors ↓ hyperactivity/impulsivity
Wang et al., 2020 [70]	Controlled, clinical trial	1010 CFU/pack/day probiotics (B. infantis, L. Rhamnosus, B. lactis, L. paracasei) + FOS	26 (3 to 9 years)	12 months	↓ severity of autism ↓ GI symptoms
Javadfar et al., 2020 [71]	Randomized, clinical trial	300 UI/kg (max 6000 UI/day) vit. D	43 (8.41 ± 2.87 years)	15 weeks	Improved CARS Improved ATEC
Boone et al., 2020 [72]	Secondary analysis of a randomized trial not available	200 mg/day DHA + 200 mg/day AA	377 (10–16 months of age born at ≤35 weeks of gestation)	26 weeks	No differences (caregiver reported)
Renard et al., 2020 [73]	Randomized, placebo-controlled trial	10 mg/day folinic acid	19 children (3 to 10 years)	12 weeks	Improved ADOS score
Kong et al., 2021 [74]	Randomized, double-blinded, placebo-controlled pilot trial	6 × 10 10 CFU/day (L. plantarum PS128) + oxytocin (dosage not available)	35 (3 to 20 years)	28 weeks	↓ ABC ↓ SRS ↓ CGI
Doaei et al., 2021 [75]	Randomized, clinical trial	1 g/day omega-3	54 children (5 to 15 years)	8 weeks	↓ stereotyped behaviors improve social communication ↓ GARS score
Batebi et al., 2021 [76]	Randomized, double-blind, placebo-controlled trial	2 mg/kg (up to 50 mg)/day folinic acid + risperidone (initiating dose of 0.5 mg/day with a dose increase of 0.5 mg per week, maximum 1.5 mg/day)	55 children (4 to 12 years)	10 weeks	↓ inappropriate speech ↓ stereotypic behavior ↓ hyperactivity/noncompliance
Boone et al., 2022 [77]	Secondary analysis of a randomized clinical trial not available	338 mg EPA + 225 mg DHA + 83 mg GLA + 280 mg omega-6 + 306 mg omega-9	31 children (18–38 months of age born at ≤29 weeks of gestation)	12 weeks	↓ depressive behavior ↓ internalizing behavior ↓ interpersonal relationship adaptive behavior
Keim et al., 2022 [78]	Randomized, double-blind, controlled trial	112 mg EPA+ 67 mg DHA+ 122 mg omega-6 (included 32 mg GLA) + 83 mg omega-9	72 (2 to 6 years)	12 weeks	Reduction of IL2 level
Schmitt et al., 2023 [79]	Randomized, controlled trial	2 × 10 10 CFU L. Reuteri + 200 mg Sepadex® (dextran microparticles) + 74 mM maltose/day	15 (15 to 45 years)	4 weeks	↓ adaptive behavior ↓ social preference

Abbreviations: EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; Vit. D = vitamin D; AA = arachidonic acid; GI = gastrointestinal; FOS = fructo-oligosaccharide; IL = interleukin; GLA = gamma-linolenic-acid; FMT = fecal microbiota transplant; GARS = Gilliam Autism Rating Scale-second edition; MTT = Microbiota transfer therapy; SRS-2 = Social Responsiveness Scale Improve Social; CBCL = Child Behavior Checklist; ASD = autism spectrum disorder; CFU = colony-forming unit; L. = lactobacillus; B. = bifidobacterium; CARS = Childhood Autism Rating Scale; ATEC = Autism Treatment Eval‎uation Checklist; CGI = Clinical Global Impression; ABC = Autistic Behavior Checklist; ADOS = Autism Diagnostic Observation Schedule; ↓ = improvement of.

Table 3. Major Depression Disorder.

Table 3. Major Depression Disorder.

Major Depression DisorderStudyStudy DesignDrugs and DoseCohortTreatmentDurationResults

Ginty et al., 2015 [80]	Preliminary randomized and placebo-controlled trial	1.4 g/day omega-3 (EPA + DHA) monotherapy	23 (18 to 21 years)	3 weeks	↓ BDI scores over time
Mischoulon et al., 2015 [81]	Randomized, double-blind, placebo-controlled trial	1 g/day EPA or 1 g/day DHA or placebo	196 (age not available)	8 weeks	No differences
Park et al., 2015 [82]	Randomized, double-blind, placebo-controlled trial	1140 g/day EPA + 0.6 g/day DHA + standard therapy	35 (18 to 65 years)	12 weeks	No differences
Rapaport et al., 2016 [83]	Proof-of-concept study	1060 mg/day EPA + 260 mg DHA or 180 mg EPA + 900 mg/day DHA or placebo	155 (18 to 80 years)	8 weeks	Subjects with MDD and a high number of inflammatory biomarkers had a better response to EPA than the placebo and a lower response to DHA than the placebo
Young et al., 2017 [84]	Randomized, placebo-controlled trial	1.4 g/day EPA + 0.2 g/day DHA + 0.4 g/day other omega-3 + IF-PEP	72 (7 to 14 years)	12 weeks	↓ co-occurring behavior symptoms
Gabbay et al., 2018 [85]	Double-blind, placebo-controlled trial	2:1 ratio of EPA to DHA: Initial dose of 1.2 g/day. Doses were raised in increments of 0.6 g/day every 2 weeks (maximum possible dose of 3.6 g/day, combined 2.4 g EPA + 1.2 g DHA)	51 psychotropic medication-free adolescents with MDD (12 to 19 years)	10 weeks	No differences
Jahangard et al., 2018 [86]	Randomized, double-blind, placebo-controlled trial	1000 mg/day omega-3 + 50–200 mg/day sertraline	50 (18 to 65 years)	12 weeks	↓ depression, anxiety, sleep, and patients’ competencies to regulate their emotions
Hansen et al., 2019 [87]	Randomised, multicenter, double-blind, placebo-controlled trial	2800 UI /day Vit. D	62 (18 to 65 years)	12 weeks (+12 weeks follow up)	No differences
Tayama et al., 2019 [88]	Randomized, double-blind, placebo-controlled trial	1000 mg/day EPA + 500 mg/day DHA	20 (18 to 75 years)	12 weeks	No differences
Chahwan et al., 2019 [89]	Randomized, triple-blind, placebo-controlled trial	Ecologic®Barrier (B. bifidum W23, B. lactis W51, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24, L. lactis W19 and L. lactis W58 (total cell count 1 × 1010 CFU/day)	71 (23 to 48 years)	8 weeks	No differences
Parletta et al., 2019 [90]	Randomized, placebo-controlled trial	200 mg/day EPA + 900 mg/day DHA + Mediterranean-style diet	152 (18 to 65 years)	26 weeks	↓ depressive symptoms ↓ mental health
Karakula-Juchnowicz et al., 2019 [91]	Double-blind, placebo-controlled clinical study protocol	3 × 109 CFU L. helveticus Rosell®-52 + B. longum	120 (18 to 60 years)	12 weeks	↓ GI symptoms ↓ depressive symptoms
Kazemi et al., 2019 [92]	Randomized, controlled trial	L. helveticus + B. longum (probiotic) or galactooligosaccharides (prebiotics) or placebo	110 (36.5 ± 8.03 years)	8 weeks	Probiotics: ↓ BDI Prebiotics: no differences
De Koning et al., 2019 [93]	Randomized, placebo-controlled trial	1200 UI/day Vit. D	155 (60 to 80 years)	52 weeks	Increase of Vit. D serum level No clinical differences
Alavi et al., 2019 [94]	Randomized clinical trial	50,000 IU/week Vit. D	78 older adults aged over 60 years	8 weeks	Increase of Vit. D serum level ↓ GDS-15
Saccarello et al., 2020 [95]	Randomized, double-blind, placebo-controlled Study	200 mg/day SAMe + 1 × 10⁹ CFU/day L. plantarum HEAL9	90 (18 to 60 years)	6 weeks	↓ Z-SDS
Trebatickà et al., 2020 [96]	Randomized, double-blind, placebo-controlled trial	2.4 g/day omega-3 (including 1 g EPA + 0.75 g DHA) or 2.467 g/day omega 6 (linoleic acid)	60 children suffering from depressive disorder or mixed anxiety and depressive disorder (7 to 18 years)	12 weeks	↓ CDI score ↓ omega 6/omega-3
Reininghaus et al., 2020 [97]	Randomized, placebo-controlled trial	B. bifidum W23 + B. lactis W51 + B. lactis W52 + L. acidophilus W22 + L. casei W56 + L. paracasei W20 + L. plantarum W62 + L. salivarius W24 + L. lactis W19 daily	82 (18 to 75 years)	4 weeks	No differences
Reiter et al., 2020 [98]	Monocentric, randomized, placebo-controlled trial	B. bifidum W23 + B. lactis W51+ B. lactis W52 + L. acidophilus W22 + L. casei W56 + L. paracasei W20 + L. plantarum W62 + L. salivarius W24 + L. lactis W19 daily	61 (18 to 75 years)	4 weeks	Reduction of IL6 level
Kaviani et al., 2020 [99]	Randomized, double-blind, placebo-controlled trial	50,000 IU/ 2 weeks vit. D	56 (43 ± 11.15 years)	8 weeks	↓ depressive symptoms Increase of serum vit. D level
Zhu et al., 2020 [100]	Randomized, placebo-controlled trial	1600 mg/day Vit D	158 with hypovitaminosis D (18 to 60 years)	26 weeks	No differences in depression symptoms; improved anxiety symptoms
Libuda et al., 2020 [101]	Randomized, placebo-controlled trial	2640 UI vit. D/day	113 with hypovitaminosis D (18 to 60 years)	4 weeks	Increase of serum vit. D level ↓ DISYPS
Ho et al., 2021 [102]	Randomized, double-blind, placebo-controlled pilot trial	2 capsules (3 × 1010 CFU) L. Plantarum PS128	40 non-depressed patients with insomnia (20 to 40 years)	4 weeks	↓ BDI ↓ awakenings during the deep sleep stage
Joo Lee et al., 2021 [103]	Randomized, double-blind, placebo-controlled Trial	5 × 109 CFU probiotics (4.0 × 109 CFU for L. reuteri NK33 + 1 × 109 CFU for B. adolescentis NK98)	156 healthy adults with subclinical symptoms of depression, anxiety, and insomnia (19 to 65 years)	8 weeks	↓ quality of sleep ↓ IL-6 ↓ depressive symptoms at 4 and 8 weeks of treatment ↓ anxiety symptoms at 4 weeks
Mischoulon et al., 2022 [104]	Randomized, dose-finding clinical trial	1 g/day or 2 g/day or 4 g/day EPA	61 (age not available)	12 weeks	4 g/day EPA: ↓ depressive symptoms ↓ hs-CRP
Kaviani et al., 2022 [105]	Randomized, double-blind, placebo-controlled trial	50,000 IU cholecalciferol/2 weeks-1	56 (18 to 60 years)	8 weeks	Increase of Vit. D serum level ↓ depressive symptoms
Schaub et al., 2022 [106]	Randomized, placebo-controlled trial	900 billion CFU/day (S. thermophilus + B. breve + B. longum + B. infantis + L. acidophilus + L. plantarum + L. paracasei + L. delbrueckii subsp. Bulgaricus) + treatment-as-usual	47 (over 18 years)	4 weeks	↓ depressive symptoms
Ullah et al., 2022 [107]	Monocentric, randomized, cross-over, double-blind, placebo-controlled clinical trial	200 mg/day SAMe + 3 × 109 CFU/day L. helveticus Rosell®-52 + B. longum Rosell®-175	80 patients with SD or MDD (18 to 65 years)	12 weeks	↓ SD symptoms ↓ MDD symptoms
Schneider et al., 2023 [108]	Secondary analysis of a randomized, placebo-controlled trial	Bifidobacteria 9 × 1010 CFU/g + Lactobacilli 8 × 1010 + S. salivarius subsp. Thermophilus 20 × 1010 resulting in a daily dose of 900 billion CFU/d + usual depression treatment	60 (over 18 years)	4 weeks	↓ cognitive function (verbal episodic memory and working memory)
Nikolova et al., 2023 [109]	Single-center, double-blind, placebo-controlled pilot randomized clinical trial	2 × 109 CFU B. subtilis, B. bifidum, B. breve, B. infantis, B. longum, L. acidophilus, L. delbrueckii subsp bulgaricus, L. casei, L. plantarum, L. rhamnosus, L. helveticus, L. salivarius, L. lactis and S. thermophilus	49 MDD taking antidepressant medication, but having an incomplete response were studied (18 to 55 years)	8 weeks	↓ depressive symptoms ↓ anxiety symptoms
Zhu et al., 2023 [110]	Randomized, placebo-controlled trial	L. plantarum JYLP-326 2 vv/day	60 anxious 22-year-old students	3 weeks	↓ depression ↓ anxiety ↓ insomnia

Abbreviations: EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; MDD = Major depressive disorder; BDI = Beck Depression Inventory; GI = Gastrointestinal; CFU = colony forming units; HDRS = Hamilton depression rating scale; SAMe = S-adenosylmethionine; Z-SDS = Zung Self-Rating Depression Scale; SD = Subthreshold depression; GDS-15 = Geriatric Depression Scale-15; DISYPS-II = diagnostic system for mental disorders in childhood and adolescents, self-hand parent rating; CDI = Children’s Depression Inventory; IF-PEP = individual–family psychoeducational psychotherapy; B. = bifidobacterium or Bacillus; L. = Lactobacillus or Lactococco; S. = Streptococcus; Vit. = vitamin; IL = interleukin; ↓ = improvement of; hs-CRP = hs-C reactive protein.

Table 4. Bipolar Disorder.

Table 4. Bipolar Disorder.

Bipolar DisorderStudyStudy DesignDrugs and DoseCohortTreatmentDurationResults

Sharpley et al., 2014 [111]	Randomized, double-blind, placebo-controlled trial	2.5 mg/day folic acid	112 with familial risk of mood disorder (14 to 24 years)	156 weeks	No differences
Fristad et al., 2015 [112]	Randomized, placebo-controlled trial	2000 mg/day omega-3 (including 1400 mg EPA + 200 mg DHA) and IF-PEP vs. AM using a 2 × 2 design	23 (7 to 14 years)	12 weeks	Manic symptoms improved over time without significant treatment effects Effect of IF-PEP on child depression compared with AM was medium to large Effect of omega-3 on depression was medium
Wozniak et al., 2016 [113]	Pilot study	1650 mg/day EPA + DHA + 2000 mg inositol or 1650 mg/day EPA + DHA + placebo or 2000 mg inositol + placebo	24 (5 to 12 years)	12 weeks	Omega-3 + inositol: ↓ symptoms of mania and depression
Marsh et al., 2017 [114]	Randomized, double-blind, placebo-controlled trial	5000 UI/day Vit. D	33 patients with vit. D deficiency (18 to 70 years)	12 weeks	No differences in depressive symptoms
Nierenberg et al., 2017 [115]	Open trial proof-of-concept registry	15 mg/day L-methyl folate	10 (18 to 75 years)	6 weeks	↓ MADRS ↓ Cohen’s d ↓ YMRS
Dickerson et al., 2018 [116]	Randomized, parallel two-group, placebo-controlled trial	L. rhamnosus strain GG + B. animalis subsp. Lactis strain Bb12 (dosage not available)	66 patients who have been recently discharged following hospitalization for mania (18 to 65 years)	24 weeks	↓ rehospitalization
Mehrpooya et al., 2018 [117]	Double-blind placebo-controlled trial	200 mg/day Coenzyme Q10	69 (18 to 65 years)	8 weeks	↓ depressive symptoms
Vesco et al., 2018 [118]	Randomized controlled trial	1.87 g/day omega-3 or PEP or PEP + omega-3	95 (7 to 14 years)	12 weeks	Omega-3: ↓ executive functions ↓ dysphoric mood ↓ irritability ↓ self-esteem
Toniolo et al., 2018 [119]	Double-blind, placebo-controlled trial	6 g/day creatine monohydrate	35 (18 to 59 years)	6 weeks	No differences
McNamara et al., 2020 [120]	Placebo-controlled proton magnetic resonance spectroscopy trial	2130 mg/day omega-3 (EPA + DHA)	42 children with depressive symptoms with at least one parent with DB (9 to 21 years)	12 weeks	No clinical differences Increase of erythrocyte EPA + DHA levels
Ashton et al., 2020 [121]	Sub-study, randomized, placebo-controlled trial	N-acetyl-cysteine or mitochondrial-enhancing nutraceuticals (including N-acetyl-cysteine)	133 (21.3 to 72 years)	16 weeks	Better diet quality (irrespective of treatment and time): ↓ general depression and bipolar depression symptoms Greater clinician-rated improvement
McPhilemy et al., 2021 [122]	Randomized, placebo-controlled trial	1 g/day EPA+ 1 g/day DHA	80 (over 18 years)	52 weeks	No differences
Badrfam et al., 2021 [123]	Randomized, double-blind, placebo-controlled trial	80 mg/day vit. B6 + lithium (gradually increased dose to a therapeutic level of 0.8–1.2)	50 (18 to 65 years)	8 weeks	No differences
Fristad et al., 2021 [124]	Naturalistic follow-up study	2000 mg/day omega-3 (including 1400 mg EPA + 200 mg DHA) and IF-PEP vs. AM using a 2 · 2 design	38 (11 to 19 years)	104–260 weeks	↓ depressive symptoms ↓ youth emotion regulation skills and family communication
Sabouri et al., 2022 [125]	Randomized, double-blind, placebo-controlled trial	Probiotics	38 (age not available)	8 weeks	No differences in markers of inflammation and oxidative stress
McNamara et al., 2022 [126]	Placebo-controlled trial	2130 mg/day omega-3 (EPA + DHA)	39 depressed youth at high risk for developing BD type I (9 to 21 years)	12 weeks	↓ functional amygdala–right inferior temporal gyrus connectivity ↓ depressive symptoms Increase of erythrocyte EPA + DHA levels
Saunders et al., 2022 [127]	Randomized, parallel-group, modified double-blind, controlled	1.5 g omega-3 (EPA + DHA) + low omega-6 vs. control diet standardized (150 mg omega-3 + omega-6)	82 (over 18 years)	48 weeks (4-8-12 weeks of diet exposure)	No differences
Wozniak et al., 2022 [128]	Randomized, double-blind, placebo-controlled trial	1650 mg/day EPA + DHA + 2000 mg inositol or 1650 mg/day EPA + DHA + placebo or 2000 mg inositol + placebo	69 (5 to 12 years)	12 weeks	↓ YMRS (inositol + omega-3) ↓ HDRS (inositol + omega-3) ↓ antimanic and antidepressant effects
Eslahi et al., 2023 [129]	Randomized, double-blind, placebo-controlled trial	2 g/day omega-3 (including 180 mg EPA + 120 mg DHA)	60 (16 to 60 years)	8 weeks	↓ depression score ↓ TNF-α ↓ IL-6 ↓ hs-CRP
Zailani et al., 2024 [130]	Pilot randomized, placebo-controlled trial	420 mg/day EPA + 220 mg/day DHA + 0.2 mg/day tertiary-butylhydroquinone + 2.0 mg/day vit. E	31 (18 to 65 years)	26 weeks	↓ recurrence of bipolar depression ↓ depressive symptoms
Zandifar et., 2024 [131]	Randomized, placebo-controlled trial	100 mg/day vit. B1 or 40 mg/day vit. B6 or placebo + 900–1200 mg lithium	66 (18 to 65 years)	8 weeks	B6: ↓ symptoms during a manic episode + ↓ sleep status B1: no mood improvement, ↓ sleep status

Abbreviations: EPA = Eicosapentaenoic acid; DHA = Docosaesaenoic acid; IL-6 = interleukin 6; YMRS = Young Mania Rating Scale; HDRS = Hamilton Depression Rating Scale; Vit. = vitamin; CFU = colony-forming unit; L. = lactobacillus; B. = bifidobacterium; ↓ = improvement, IF-PEP = individual–family psychoeducational psychotherapy; AM = active monitoring; MADRS = Montgomery–Asberg Depression Rating Scale; DPA = n-3 docosapentaenoic acid; BD = Bipolar Disorder; hs-CRP = hs-C reactive protein; TNF = tumor necrosis factor.

Table 5. Borderline Personality Disorder.

Table 5. Borderline Personality Disorder.

Borderline Personality DisorderStudyStudy DesignDrugs and DoseCohortTreatment durationResults

Bellino et al., 2014 [132]	Randomized, controlled trial	1.2 g/day EPA + 0.6 g/day DHA + 800–1300 mg/day valproic acid vs. 800–1300 mg/day valproic acid (plasma range: 50–100 μg/mL)	43 BPD patients (18 to 50 years)	12 weeks	↓ severity of BPDSI ↓ impulsive behavioral dyscontrol ↓ anger ↓ self-mutilating conduct
Bozzatello et al., 2018 [133]	Follow-up study to Bellino et al., 2014	1.2 g/day EPA + 0.6 g/day DHA + 800–1300 mg/day valproic acid vs. 800–1300 mg/day valproic acid (plasma range: 50–100 μg/mL)	34 patients with BPD (18 to 50 years)	24 weeks	↓ outbursts of anger
Raine et al., 2021 [134]	Randomized, double-blind, placebo-controlled Trial	300 mg DHA + 300 mg EPA + 180 mg alpha-linolenic acid + 60 mg DPA	324 children (11.89 years (SD 2.59))	52 weeks	↓ aggression, ↓ antisocial behavior

Abbreviations: EPA = eicosapentaenoic acid; DHA = docosahexaenoic acid; DPA = n-3 docosapentaenoic acid; BPDSI = borderline personality disorder severity index; ↓ = improvement of.

3. Results

Records from PubMed and study screening are displayed in the following flowchart (Figure 2).

Figure 2. Literature search flowchart.

4. Discussion

4.1. Schizophrenia

Schizophrenia is a psychotic disorder with a clinical picture defined by five symptom domains: delusions, hallucinations, disorganized thinking, disorganized behaviors, and negative symptoms. The syndrome must be present continuously for more than six months and has usually a chronic course [135,136,137]. To eval‎uate the effects of omega-3 fatty acids and nutraceuticals in the different phases of schizophrenia, investigations were conducted in subjects at high risk of developing psychosis, patients with their first psychotic episodes, and patients with chronic phases.

Studies indicated that the etiology and severity of schizophrenia may be influenced by genetic abnormalities in the metabolism of fatty acids, prostaglandins, and phospholipids [138,139]. They were observed in the early phases of the disease also before the onset of psychotic symptoms [140]. In both chronic and non-medicated first-episode patients with psychosis, unsaturated fatty acid levels were found to be significantly reduced in the erythrocyte membranes and the post-mortem brain tissue in comparison to healthy controls [141,142,143,144,145]. A decrease in the proportion of omega-3 fatty acids in the cellular membranes was also associated with worse functioning before the onset of psychosis [145] and could be linked with greater severity of symptoms and poor therapeutic response [146,147]. A significant relationship was observed between lower erythrocyte essential fatty acid concentration and greater severity of negative symptoms [140,148], cognitive impairment, and tardive dyskinesia [149].

4.1. 정신분열증

정신분열증은

망상, 환각, 사고 혼란, 행동 혼란, 음성 증상이라는

다섯 가지 증상 영역으로 정의되는 임상 양상을 보이는 정신병적 장애이다.

delusions, hallucinations, disorganized thinking, disorganized behaviors, and negative symptoms

이 증후군은 6개월 이상 지속적으로 존재해야 하며 일반적으로 만성 경과를 보인다 [135,136,137]. 정신분열증의 다양한 단계에서 오메가-3 지방산 및 기능성 식품의 효과를 평가하기 위해, 정신병 발병 고위험군 대상자, 첫 번째 정신병 에피소드를 경험한 환자, 만성기 환자를 대상으로 연구가 수행되었다.

연구에 따르면, 정신분열증의 발병 기전과 중증도는 지방산, 프로스타글란딘, 인지질 대사에 대한 유전적 이상에 의해 영향을 받을 수 있다[138,139]. 이러한 이상은 정신병적 증상 발현 이전인 질병 초기 단계에서도 관찰되었다[140]. 만성 정신병 환자 및 비약물 치료 초발 정신병 환자 모두에서, 적혈구 막 및 사후 뇌 조직 내 불포화 지방산 수치가 건강한 대조군에 비해 현저히 감소한 것으로 나타났다[141,142,143,144,145]. 세포막 내 오메가-3 지방산 비율의 감소는 또한 정신병 발병 전 기능 저하와 연관되었으며[145], 증상 중증도 증가 및 치료 반응 저하와도 관련될 수 있다[146,147]. 적혈구 필수 지방산 농도가 낮을수록 음성 증상[140,148], 인지 장애 및 지연성 운동 이상증[149]의 중증도가 높아지는 유의미한 상관관계가 관찰되었습니다.

In the past, it was observed that between 22% and 40% of adolescents and young adults who are classified as high-risk or ultra-high-risk (UHR) of psychosis underwent a transition to psychosis within three years after the first examination [150,151,152]. These data indicate the need for diagnostic and therapeutic interventions to prevent the onset of psychosis [153]. Some authors [145] analyzed the correlation between metabolic abnormalities and the risk of psychosis (eval‎uated using the Scale of Prodromal Symptoms (SOPS) from the Structured Interview for Prodromal Symptoms (SIPS)) and found that over 90% of high-risk subjects in the cohort showed elevated oxidative stress. They found a relatively low (<4%) red blood cell omega-3 fatty acids index and a significant association between cardiometabolic abnormalities, lower levels of omega-3 fatty acid intakes, and increased severity of symptoms and impairment of functioning, suggesting that dietary factors and systemic illness may play a role in the psychosis disease process. Consequently, since it is debatable whether to treat young people at risk of psychosis with antipsychotic drugs [154], therapy with omega-3 fatty acids and nutraceuticals, having no clinically noteworthy negative side effects, can be discussed as a possible initial treatment for these subjects.

Eighteen trials eval‎uating omega-3 fatty acids administration in UHR subjects [28,29,30,31,32], patients with first-episode psychosis [33,34,35,36,37,40,43], and stable schizophrenia patients [45,47,48,50,51] have been performed over the past decade.

과거 연구에서 정신병 고위험군 또는 초고위험군(UHR)으로 분류된 청소년 및 청년의 22~40%가 최초 검사 후 3년 이내에 정신병으로 전환되는 것으로 관찰되었다[150,151,152]. 이러한 데이터는 정신병 발병을 예방하기 위한 진단적·치료적 개입의 필요성을 시사한다[153]. 일부 연구자[145]는 대사 이상과 정신병 위험(구조화된 전구증상 인터뷰(SIPS)의 전구증상 척도(SOPS)로 평가) 간의 상관관계를 분석한 결과, 코호트 내 고위험군의 90% 이상에서 산화 스트레스가 증가한 것으로 나타났다. 그들은 적혈구 오메가-3 지방산 지수가 상대적으로 낮음(<4%)을 발견했으며, 심혈관 대사 이상, 낮은 오메가-3 지방산 섭취 수준, 증상 중증도 증가 및 기능 장애 사이의 유의한 연관성을 확인하여 식이 요인과 전신 질환이 정신병 발병 과정에 역할을 할 수 있음을 시사한다. 따라서 정신병 위험이 있는 젊은이들을 항정신병 약물로 치료할지 여부는 논란의 여지가 있으므로 [154], 임상적으로 주목할 만한 부작용이 없는 오메가-3 지방산 및 기능성 식품을 이용한 치료가 이러한 대상자들을 위한 가능한 초기 치료법으로 논의될 수 있다.

지난 10년간 초고위험군(UHR) 대상자[28,29,30,31,32], 초발 정신병 환자[33,34,35,36,37,40,43], 안정된 정신분열증 환자[45,47,48,50,51]를 대상으로 오메가-3 지방산 투여를 평가한 18건의 임상시험이 수행되었다.

Five of these studies eval‎uated the administration of EPA (between 700 and 840 mg) and DHA (between 480 and 560 mg) in UHR subjects [28,29,30,31,32]. The results showed that omega-3 fatty acids improved inflammatory and blood profiles [28,31] and reduced the risk of progression to psychotic disorder [29]. In a post hoc study [29], they also showed that most individuals in the omega-3 fatty acids group did not show severe functional deterioration and did not experience attenuated psychotic symptoms at follow-up. On the contrary, two studies in which omega-3 fatty acids were administered in a UHR cohort showed no clinical benefits [30,32]. In a RCT [30], omega-3 fatty acids plus cognitive-behavioral case management (CBCM) or placebo plus CBCM were administered in a wide sample of young subjects at risk of developing psychosis. The authors reported an improvement in transition rates to psychosis with no significant differences between the two groups. A possible explanation could be that amelioration is obtained because of the CBCM that both groups received and that this could have hidden the effects of omega-3 fatty acids. Some authors have [32] showed a predominantly anti-inflammatory action of omega-3 fatty acids on plasma status in UHR subjects, but this effect did not appear to induce clinical benefits at 6- and 12-month follow-up.

Regarding the first episode of psychosis and omega-3 fatty acids administration, we found eight RCTs [33,34,35,36,37,40,43]. Emsley’s trial administered fatty acids as monotherapy, with no antipsychotic support [33], while trials performed by Pawelczyk and colleagues [34,35,36,37,41] tested EPA and DHA in adjunction to antipsychotics. The duration of these trials ranged from 26 weeks to 2 years. PUFA dosages ranged between 2.2 and 3 g/day. In the study [33], omega-3 fatty acids were administered to prevent relapse during antipsychotic discontinuation in remitted first-episode psychosis and did not produce significant benefits for symptom severity and functioning or relapse rate after antipsychotic discontinuation. Pawełczyk’s studies reported promising data on EPA and DHA in first-episode psychosis in terms of symptom reduction and neurobiological changes. The findings showed an improvement in general, psychotic, negative, and depressive symptoms [34,35], a decrease in the oxidative stress status of plasma with a positive effect on global and negative symptoms [35], and an increase in telomerase levels in peripheral blood cells with a positive effect on depressive symptoms and severity of illness [36,37,41].

이 중 5건의 연구는 고위험군 대상자[28,29,30,31,32]에게 EPA(700~840mg)와 DHA(480~560mg)를 투여한 결과를 평가했다. 연구 결과 오메가-3 지방산은 염증 및 혈액 프로필을 개선[28,31]하고 정신병적 장애로의 진행 위험을 감소시켰다[29]. 사후 분석 연구[29]에서는 오메가-3 지방산 투여군 대부분이 추적 관찰 시 심각한 기능 저하를 보이지 않았으며 정신병적 증상이 완화되지 않았음을 추가로 확인했다. 반면, 고위험군(UHR) 코호트에 오메가-3 지방산을 투여한 두 연구[30,32]에서는 임상적 이점이 관찰되지 않았다. 한 무작위 대조 시험[30]에서는 정신병 발병 위험이 있는 광범위한 젊은 대상군에게 오메가-3 지방산과 인지행동적 사례 관리(CBCM) 또는 위약과 CBCM을 병용 투여했다. 저자들은 정신병 전환율 개선을 보고했으나 두 군 간 유의미한 차이는 없었다. 가능한 설명으로는 양측 집단이 받은 CBCM으로 인해 증상 완화가 발생했으며, 이로 인해 오메가-3 지방산의 효과가 가려졌을 수 있다는 점이다. 일부 연구자들은 [32] 초고위험군 대상자의 혈장 상태에서 오메가-3 지방산의 주로 항염증 작용을 보여주었으나, 이 효과는 6개월 및 12개월 추적 관찰 시 임상적 이점을 유도하지 못한 것으로 나타났다.

정신병 첫 발병과 오메가-3 지방산 투여에 관해, 우리는 8건의 무작위 대조 시험(RCT)을 확인했다[33,34,35,36,37,40,43]. Emsley의 연구[33]는 항정신병 약물 지원 없이 지방산을 단독 요법으로 투여한 반면, Pawelczyk 등[34,35,36,37,41]의 연구는 항정신병 약물과 병용하여 EPA 및 DHA를 시험하였다. 이들 연구의 기간은 26주에서 2년까지 다양했으며, 다불포화지방산(PUFA) 용량은 2.2~3g/일 범위였다. [33] 연구에서는 재발성 초기 정신병 환자의 항정신병 약물 중단 시 재발 방지를 위해 오메가-3 지방산을 투여했으나, 증상 중증도 및 기능, 항정신병 약물 중단 후 재발률에 유의미한 개선 효과를 보이지 않았다. 파벨치크의 연구는 초기 정신병에서 EPA 및 DHA가 증상 감소와 신경생물학적 변화 측면에서 유망한 데이터를 보고하였다. 연구 결과는 전반적, 정신병적, 음성 및 우울 증상의 개선[34,35], 전신 및 음성 증상에 긍정적 영향을 미치는 혈장 산화 스트레스 상태의 감소[35], 우울 증상과 질병 중증도에 긍정적 영향을 미치는 말초 혈액 세포의 텔로머레이스 수준 증가[36,37,41]를 보여주었다.

It has beendemonstrated, with the MATRICS Consensus Cognitive Battery (MCCB) and the Brief Psychiatric Rating Scale (BPRS), that higher levels of omega-3 fatty acids were significantly correlated with better social cognition, while higher levels of arachidonic acid (an omega-6 fatty acid) were significantly correlated with hostility/non-cooperation [40]. In addition, patients treated with risperidone associated with omega-3 fatty acids (EPA + DHA) for 16 weeks had a significant longitudinal improvement in social cognition. The authors, therefore, provided new evidence on the differential role of omega-3 versus omega-6 fatty acids in treating the symptoms and neuropsychological deficits of recent-onset psychosis. Furthermore, it was shown that omega-3 supplementation can determine white matter MRI changes in patients with recent-onset psychosis after risperidone treatment [43].

Five RCTs were performed in patients with stable schizophrenia and omega-3 fatty acid supplementation [45,47,48,50,51]. Four studies showed a positive effect of omega-3 fatty acids on the symptom domains of schizophrenia [45,47,48,51]. The duration of the studies ranged from 8 to 16 weeks. Daily doses of PUFAs were between 0.9 and 1.4 g. EPA was found superior to placebo and DHA in reducing the psychotic symptoms [45], depressive symptoms [48], and anxious symptoms [48] of schizophrenia. One of these studies indicated that omega-3 fatty acids were useful in reducing violent behaviors, but these patients had no improvement in the positive or negative symptoms of schizophrenia [47]. In a RCT [50], it was found that the administration of omega-3 fatty acids for 12 weeks in patients with schizophrenia and metabolic syndrome improved triglyceride metabolism. Despite these encouraging initial data, it is hard to draw any conclusion on the medium- and long-term efficacy of omega-3 fatty acids in stable schizophrenia. Trials performed in the stable phase of illness have too short a duration to establish the long-lasting effects of these agents. It is interesting to note that the majority of studies found a positive effect of pure EPA or a fatty acid composition with predominantly EPA, at least when added to a stable antipsychotic treatment. Available data suggested that EPA or the composition of fatty acids with a high proportion of EPA could be more effective in the early periods of schizophrenia than in the chronic phase of the disorder. Studies using pure or predominant EPA in high-risk subjects are lacking and should be conducted. Tang et al. [51] showed that omega-3 fatty acids had beneficial effects on cognitive function in patients with metabolic syndrome, which is paralleled by enhanced brain-derived neurotrophic factor levels. These findings were consistent with the hypothesis that omega-3 fatty acid metabolism is implicated in the etiology of negative symptoms of schizophrenia [146] and with the notion that oxidative damage to lipids is connected to the process of neuroprogression and the expression‎ of negative symptoms [155].

MATRICS Consensus Cognitive Battery (MCCB) 및 Brief Psychiatric Rating Scale (BPRS)을 통해 오메가-3 지방산 수치가 높을수록 사회적 인지 능력이 향상되는 반면, 아라키돈산(오메가-6 지방산) 수치가 높을수록 적대감/비협조적 태도와 유의한 상관관계가 있음을 입증하였습니다 [40]. 또한, 리스페리돈과 오메가-3 지방산(EPA + DHA)을 16주간 병용 투여받은 환자들은 사회적 인지 기능에서 유의미한 장기적 개선을 보였다. 따라서 저자들은 최근 발병 정신병의 증상 및 신경심리학적 결손 치료에서 오메가-3와 오메가-6 지방산의 차별적 역할에 대한 새로운 증거를 제시하였다. 또한 리스페리돈 치료 후 최근 발병 정신병 환자에서 오메가-3 보충이 백질 MRI 변화를 결정할 수 있음이 입증되었다[43].

안정된 정신분열증 환자를 대상으로 오메가-3 지방산 보충제를 투여한 5건의 무작위 대조 시험(RCT)이 수행되었다[45,47,48,50,51]. 4건의 연구에서 오메가-3 지방산이 정신분열증 증상 영역에 긍정적 효과를 보였다고 보고되었다[45,47,48,51]. 연구 기간은 8주에서 16주 사이였다. 다불포화지방산(PUFA)의 일일 투여량은 0.9~1.4g이었다. EPA는 정신병적 증상[45], 우울 증상[48], 불안 증상[48] 감소 측면에서 위약 및 DHA보다 우월한 것으로 나타났다. 이 중 한 연구에서는 오메가-3 지방산이 폭력적 행동 감소에 유용함을 시사했으나, 해당 환자군에서는 조현병의 양성 또는 음성 증상 개선이 관찰되지 않았다[47]. 무작위 대조 시험(RCT) [50]에서는 조현병 및 대사증후군 환자군에 12주간 오메가-3 지방산을 투여했을 때 중성지방 대사가 개선된 것으로 나타났다. 이러한 고무적인 초기 데이터에도 불구하고, 안정기 정신분열증에서 오메가-3 지방산의 중장기적 효능에 대한 결론을 내리기는 어렵다. 질병 안정기에 수행된 임상시험들은 이러한 약제의 장기적 효과를 입증하기에는 기간이 너무 짧다. 흥미롭게도 대부분의 연구에서 순수 EPA 또는 EPA가 주성분인 지방산 조성물이 안정된 항정신병 치료에 추가될 때 긍정적 효과를 보였다는 점은 주목할 만하다. 기존 자료에 따르면 EPA 또는 EPA 비율이 높은 지방산 조성은 조현병 만성기보다 초기 단계에서 더 효과적일 수 있다. 고위험군 대상 순수 또는 주성분 EPA 연구는 부족하며 수행되어야 한다. Tang 등[51]은 오메가-3 지방산이 대사증후군 환자의 인지 기능에 유익한 효과를 보였으며, 이는 뇌유래신경영양인자(BDNF) 수치 증가와 병행된다고 밝혔다. 이러한 결과는 오메가-3 지방산 대사가 정신분열증 음성 증상의 발병 기전에 관여한다는 가설[146]과 지질의 산화적 손상이 신경 진행 과정 및 음성 증상 발현과 연관된다는 개념[155]과 일치한다.

Regarding the administration of probiotics, the literature is unfortunately scarce: there are no trials in which probiotics have been administered in UHR subjects. Huang et al., in their two trials on patients receiving olanzapine therapy at the first psychotic episode, showed that administering probiotics (Bifidobacteri, Lactobacilli, Enterococci) improved the metabolic profile of the patient and that the concomitant administration of dietary fiber helps prevent the weight gain expected when administering antipsychotic therapies such as olanzapine [44]. The other three studies on the effect of probiotics [49,53,55] showed an improvement in PANSS score [49,53] and metabolic profile [49,53,55]. In addition to probiotics, some of these studies included the concomitant administration of vitamin D [49], selenium [53], and prebiotics [55].

프로바이오틱스 투여에 관한 문헌은 안타깝게도 매우 부족하다: 초고위험군 대상자에게 프로바이오틱스를 투여한 임상시험은 존재하지 않는다. Huang 등은 첫 번째 정신병적 에피소드에서 올란자핀 치료를 받는 환자를 대상으로 한 두 건의 시험에서 프로바이오틱스(비피도박테리아, 락토바실러스, 엔테로코커스) 투여가 환자의 대사 프로필을 개선했으며, 식이섬유 병용 투여가 올란자핀과 같은 항정신병 치료제 투여 시 예상되는 체중 증가를 예방하는 데 도움이 된다는 것을 보여주었다[44]. 프로바이오틱스의 효과에 관한 다른 세 연구[49,53,55]에서는 PANSS 점수[49,53]와 대사 프로파일[49,53,55]의 개선이 관찰되었다. 프로바이오틱스 외에도, 이들 연구 중 일부는 비타민 D[49], 셀레늄[53], 프리바이오틱스[55]의 병용 투여를 포함하였다.

There are three studies investigating vitamin D supplementation [42,49,57]. No studies have been performed on UHR subjects. The randomized study by Ghaderi et al. [49], which has already been mentioned, showed an improvement in the PANSS score and metabolic profile, but this investigation included the co-administration of probiotics, so the result may not be conclusive for vitamin D. A study [42] examined adults aged 18 to 65 years within 3 years of first presentation of a functional psychotic disorder and showed no significant differences between those who received vitamin D supplementation and those receiving placebo. The study by Kalejahi et al. [57] was conducted in patients suffering from schizophrenia and hypovitaminosis D and highlighted improvements regarding the level of GSK-3 β (an important biomarker in schizophrenia) and insulin resistance.

A study [38] eval‎uated whether vitamins B6 and B12 and folic acid can lower the level of homocysteine (which is elevated in patients affected by schizophrenia and correlates with illness severity) and improve symptomatology and neurocognition in the first episode of psychosis. It showed that vitamin B supplementation for 12 weeks did not improve overall psychopathology and global neurocognition, but had specific neuroprotective properties in attention/vigilance, particularly in patients with elevated homocysteine levels, patients with affective psychosis, and female patients.

Some RCTs have been performed on molecules that prevent oxidative stress. This process and the consequent impairment of parvalbumin oligodendrocytes and interneurons may underlie alterations in brain connectivity in schizophrenia. In addition, the level of the brain antioxidant glutathione in the medial prefrontal cortex was positively related to better functional connectivity along the cingulum bundle in healthy controls, but not in patients with initial psychosis. Three RCT studies have been conducted on alpha lipoic acid (ALA, an agent with antioxidative properties) with divergent results [46,54,56]. The dosage of ALA was between 100 and 300 mg/day. Sanders’ study showed improvement in the Brief Rating Scale scores, neurocognitive parameters, and extrapyramidal symptoms and a reduction in lipid peroxidation [46]. Mishra’s study showed an improvement in the Scale for the Assessment of Negative Symptoms (SANS), but not in the Scale for the Assessment of Positive Symptoms (SAPS). Therefore, it demonstrated improvement only in negative symptoms of psychosis [54]. On the contrary, De Lima’s study found no differences between those taking ALA and the placebo group [56].

비타민 D 보충 효과를 조사한 연구는 세 건이다[42,49,57]. 초고위험군(UHR) 대상 연구는 수행된 바 없다. 앞서 언급된 Ghaderi 등의 무작위 연구[49]는 PANSS 점수와 대사 프로파일 개선을 보였으나, 이 연구는 프로바이오틱스 병용을 포함했으므로 비타민 D 단독 효과에 대한 결론적 근거로 보기 어렵다. 한 연구[42]는 기능성 정신병적 장애가 처음 나타난 지 3년 이내인 18~65세 성인을 대상으로 진행되었으며, 비타민 D 보충제를 투여받은 그룹과 위약을 투여받은 그룹 간 유의미한 차이는 나타나지 않았다. Kalejahi 등[57]의 연구는 정신분열증과 비타민 D 결핍증을 앓고 있는 환자들을 대상으로 수행되었으며, GSK-3 β 수준(정신분열증의 중요한 생체지표)과 인슐린 저항성 측면에서 개선을 강조했습니다.

한 연구[38]는 비타민 B6, B12 및 엽산이 정신분열증 환자에게서 상승하고 질병 중증도와 상관관계가 있는 호모시스테인 수치를 낮추고, 첫 번째 정신병 에피소드에서 증상 및 신경인지 기능을 개선할 수 있는지 평가했습니다. 12주간 비타민 B 보충은 전반적인 정신병리와 글로벌 신경인지 기능에는 개선 효과가 없었으나, 특히 호모시스테인 수치가 높은 환자, 정서성 정신병 환자, 여성 환자에서 주의력/경계력에 특화된 신경보호 효과를 나타냈다.

산화 스트레스를 예방하는 분자에 대한 일부 무작위 대조 시험(RCT)이 수행되었다. 이 과정과 그에 따른 파르발부민 올리고도교세포 및 중간신경세포의 손상은 정신분열증에서 뇌 연결성 변화의 기저가 될 수 있다. 또한, 내측 전전두피질의 뇌 항산화제 글루타티온 수치는 건강한 대조군에서는 띠회백질 다발을 따라 더 나은 기능적 연결성과 양의 상관관계를 보였으나, 초기 정신병 환자에게서는 그렇지 않았다. 알파 리포산(ALA, 항산화 특성을 지닌 약제)에 대한 3건의 RCT 연구가 수행되었으나 결과는 상이했다[46,54,56]. ALA 투여량은 100~300mg/일이었다. 샌더스(Sanders)의 연구에서는 간이 평가 척도 점수, 신경인지 매개변수, 추체외로 증상이 개선되고 지질 과산화가 감소한 것으로 나타났다[46]. 미슈라(Mishra)의 연구에서는 음성 증상 평가 척도(SANS)에서 개선이 나타났으나, 양성 증상 평가 척도(SAPS)에서는 개선이 관찰되지 않았다. 따라서 정신병의 음성 증상에서만 개선 효과가 입증되었다[54]. 반면, 드 리마(De Lima)의 연구에서는 ALA 투여군과 위약군 간 차이를 발견하지 못했다[56].

A randomized controlled study was carried out with N-acetyl-cysteine, a precursor of glutathione, administered for 6 months. It was found that functional connectivity increased along the cingulate and, more precisely, between the anterior caudal part and the isthmus of the cingulate cortex. Consequently, this study suggests that increasing glutathione levels in the brain through N-acetyl-cysteine supplementation may improve functional connectivity in the brain [39].

Maguire et al. tried to administer the coenzyme Q10 at a dosage of 300 mg/day for 6 months, but there were no cognitive, psychological, or health-related benefits in patients with schizophrenia and schizoaffective disorder. The study had important limitations, including poor adherence, small sample size, and attrition, that likely reduced the effect estimated. So, findings should be considered preliminary [52].

The results of the RCTs are displayed in Table 1.

글루타티온의 전구체인 N-아세틸시스테인을 6개월간 투여한 무작위 대조 연구에서, 기능적 연결성이 전두엽과 특히 전두엽 꼬리부와 전두엽 교량부 사이에서 증가한 것으로 나타났다. 따라서 본 연구는 N-아세틸시스테인 보충을 통한 뇌 내 글루타티온 수치 증가가 뇌 기능적 연결성을 개선할 수 있음을 시사한다[39].

Maguire 등은 6개월간 코엔자임 Q10을 300mg/일 용량으로 투여했으나, 정신분열증 및 정신분열정동장애 환자에서 인지적, 심리적, 건강 관련 이점은 관찰되지 않았다. 이 연구는 낮은 순응도, 작은 표본 크기, 이탈률 등 중요한 한계점을 지녀 추정된 효과를 감소시켰을 가능성이 있다. 따라서 연구 결과는 예비적이라고 간주해야 한다 [52].

무작위 대조 시험(RCT) 결과는 표 1에 제시되어 있다.

4.2. Autism Spectrum Disorders

Autism spectrum disorder (ASD) is a complex developmental disease that begins in infancy or earlier and lasts throughout the individual’s lifetime. It is characterized by stereotyped behavior and deficits in social communication, interaction, and perception [156,157]. There is no practical and targeted treatment for ASD, which has become a major worldwide health problem [158]. In fact, current treatment encompasses mainly education and rehabilitation interventions, without significant improvement in the core symptoms. The etiology and mechanisms of ASD are not yet completely understood. Many studies suggested a possible link between ASD and multiple environmental as well as genetic risk factors [159]. Moreover, increasing evidence supports the hypothesis that children who suffer from autism are more likely to experience inconvenience related to the gastrointestinal tract (GIT), including food allergies, dysbiosis, inflammatory bowel disease, and indigestion [160]. Gastrointestinal disturbances are commonly encountered comorbidities that are thought to be not only another symptom of ASD but also to play an active role in modulating the expression‎ of social and behavioral symptoms. Therefore, nutritional interventions are used by patients with ASD to alleviate gastrointestinal and behavioral symptoms, but there is no consensus regarding optimal nutritional therapy [161].

There is a general agreement on the significant role of omega-3 fatty acid metabolism in neurodevelopmental disorders and symptom improvement. Even in ASD, as in other psychiatric disorders, low plasma levels of omega-3 fatty acids have been found [162,163].

Eight studies have been identified exploring the effect of omega-3 fatty acid supplementation in ASD [58,59,60,61,66,68,75,78]. Among them, four reported an improvement in ASD symptoms [85,86,87,88]. In these studies, 722 mg to 1.3 g of omega-3 fatty acids/day were administered in rather wide cohorts of children. The duration of trials varied from 6 weeks to 12 months. They showed improvement in hyperactivity [58], irritability [68], stereotyped behaviors, social communication, and Gilliam Autism Rating Scale (GARS) [75]. In the study performed by Ooi et al. [61], post-treatment, blood fatty acid levels were significantly correlated with changes in the core symptoms of ASD, and baseline levels of blood fatty acids were also predictive of response to the omega-3 fatty acid treatment. Moreover, ASD symptoms were positively correlated with cytokine and chemokine levels in the bloodstream and cerebral spinal fluid [164]. Two trials tested fatty acid supplementation and examined inflammatory markers for changes in behavior [60,68]. Mankad et al. suggested worsened externalizing behaviors with increasing levels of IL-10 and IL-1β but no clear path connecting supplementation to changes in cytokines and to subsequent behavior [60]. Similarly, in another study they [68] tested interactions between baseline IL-1β levels and treatment assignment but did not measure changes in inflammation due to treatment. The mechanisms by which fatty acids might improve ASD symptoms are not well understood, which led us to hypothesize that omega-3 fatty acid supplementation would interrupt detrimental neurological pathways by reducing inflammation. Keim et al. [78] eval‎uated the effect of omega-3 and omega-6 fatty acid supplementation for 90 days in children (ages 2 < 6 years) recently diagnosed with ASD. The authors found that treatment increased omega-3 and omega-6 fatty acid levels (1.40 mol% for EPA and 1.62 mol% for DHA) and reduced IL-2 levels compared to placebo (−0.17 pg/mL, 95% CI −0.31, −0.02, d = −0.62).

Discordant results were reported by three other placebo-controlled studies [91,92,93] that showed no significant differences between treated patients and controls in autism symptoms. These studies were conducted in smaller cohorts of children, with a daily omega-3 fatty acid dosage of 0.75 g to 1.5 g for a period of 2–6 months. In two RCTs [60,66], the administration of EPA + DHA was envisaged, while in another trial [59], the administration of 0.2 g/day of DHA was provided in monotherapy.

Parellada and colleagues [66] investigated omega-3 fatty acid supplementation in ASD for 8 weeks (962 mg/d and 1155 mg/d for children and adolescents, respectively). Treatment with omega-3 fatty acids improved the erythrocyte membrane omega-6/omega-3 ratio in comparison to the placebo group. Nevertheless, the authors did not find a significant difference in behavioral measures (Social Motivation and Social Communication subscale scores) between groups.

A growing number of studies suggested the importance of probiotics in improving the balance of the gut microbiota and therefore the symptoms of ASD. For this reason, some studies have been carried out in which probiotics were administered [62,63,69,70,74,79]. In these RCTs, several nutraceuticals were administered, at different doses, including stumps of Lactobacillus, Bilidumbacteria, and Streptococcus. The observation period ranged from 1 to 12 months. These studies stated that intake of probiotics resulted in a better Bacteroidetes/Firmicutes ratio [62] and improvement of gastrointestinal symptoms [63,70], autism symptoms [63,70,74], disruptive and rule-breaking behaviors [69], hyperactivity/impulsivity [69], adaptive behaviors [79], and social preference [79]. In addition to probiotics, maltose [79], fructo-oligosaccharide [70], and oxytocin [74] were also administered in some studies.

A small open-label clinical trial eval‎uated the impact of microbiota transfer therapy (MTT) on gut microbiota composition and gastrointestinal and ASD symptoms of children diagnosed with ASD. MTT involved a 2-week antibiotic treatment, intestinal cleansing, and then extended fecal microbiota transplantation (FMT) using a high initial dose followed by daily and lower maintenance doses for 7–8 weeks. After MTT, ASD behavioral symptoms and gastrointestinal symptoms improved. The changes persisted for at least 8 weeks after the end of treatment, suggesting a long-term benefit [65].

Furthermore, integrative therapy with vitamin D has been attempted [68,71], in monotherapy [71] or in association with fatty acids [68], with a dosage range from 2000 IU/day to 6000 IU/day for a period of 12–15 weeks. In the study by Javadfar et al., the scores of the Childhood Autism Rating Scale (CARS) and the Autism Treatment Eval‎uation Checklist (ATEC) significantly improved, while the Adult Behavior Checklist (ABC-C) score and serum levels of serotonin and IL-6 were unchanged. Mazahery and collaborators [71] showed a reduction in irritability and hyperactivity, but it must be considered that in this study children received omega-3 fatty acids in association with vitamin D.

Since folate plays a key role in neural development during the embryonic and fetal period and in the first years of life [165,166], high-dose folinic acid was also taken into consideration and showed an improvement in verbal communication in children with ASD. Two recent studies [73,76] tested the effect of folinic acid supplementation in a sample of children with autism. The dosage of folinic acid ranged from 10 to 50 mg/day and the duration of the studies ranged from 10 to 12 weeks. It should be noted that in the study by Batebi et al. [76], folinic acid was administered concomitantly with the antipsychotic risperidone, while in another RCT [73], it was provided in monotherapy or without changes in therapeutic management in the 8 weeks preceding the study. The findings showed an improvement in the Autism Diagnostic Observation Schedule (ADOS) score [73], inappropriate speech, stereotypic behavior, and hyperactivity/noncompliance [76]. On the other hand, no differences were recorded regarding irritability and lethargy/social withdrawal [76].

Some evidence supported the hypothesis that children born extremely preterm had a higher risk of developing ASD and associated behaviors than children born at a later gestational age [167,168,169,170]. Four studies were conducted to assess the risk of developing ASD in children born prematurely [64,67,72,77]. Omega-3-6-9 fatty acids were administered at doses ranging between 0.5 g and 1 g. The follow-up period ranged from 13 to 26 weeks. These compounds showed a beneficial effect on early language development [64], interpersonal relationship adaptive behavior [77], and ASD symptoms measured with the Brief Infant Toddler Social Emotional Assessment (BITSEA) ASD scale [67]. On the contrary, the study by Boone et al. [72] performed in a larger cohort of children did not find significant differences between cases and controls.

Data obtained from studies of autism spectrum disorders are summarized in Table 2.

4.3. Major Depression

Major depressive disorder (MDD) is an episodic and recurrent disorder characterized by evident depression of mood and loss of interest, as well as significant deterioration of cognitive abilities and autonomic functions, lasting more than two weeks, but usually several months. There is commonly remission between two episodes. The treatment of major depressive episodes is mainly based on monoaminergic medications. However, despite the presence of several antidepressant drugs, their effectiveness in some patients is still partial. A promising intervention to improve antidepressant treatment could be the use of adjunctive nutraceuticals which are now considered a versatile, tolerable, and effective adjunctive treatment to reduce the impact of depressive symptoms and improve the functioning of MDD patients [171].

Some investigations reported that patients with MDD have a lower level of EPA and DHA in their peripheral tissues (plasma, serum, and red blood cells) than control subjects [172,173]. A dietary intake of omega-3 fatty acids could be linked to a decreased risk of MDD [173,174,175,176,177] and improvement in white matter integrity [178]. Moreover, the anti-inflammatory properties of omega-3 fatty acids, particularly EPA, could be crucial to preventing the onset of depression [179]. The available evidence suggests that depression rates are rising among children and adolescents, potentially driven by alterations in environmental factors [180]. One of these factors could be the change in eating habits, with the consumption of high-energy and nutrient-poor foods, as well as the abandonment of traditional diets that included a greater intake of plant foods and quality proteins [181]. This change has resulted in an increased consumption of omega-6 and a depletion of omega-3 fatty acids [182], which leads to an imbalance of fatty acid composition in plasma and erythrocytes, with a negative impact on central nervous system neuronal membranes and serotonin transport. Available data suggested a relationship between low levels of EPA and DHA and depressive symptoms in adulthood [173,183,184]. Therefore, EPA and DHA can exert antidepressant, anti-inflammatory, and neuroprotective properties, although the exact molecular mechanism underlying their effects is not yet completely clear.

In the last decade, eleven RCTs have been carried out on the effects of omega-3 fatty acids in treating major depression [80,81,82,83,84,85,86,88,90,96,104]. Fatty acids were administered both in monotherapy and as supplementation to ongoing pharmacotherapy or psychotherapy. The majority of studies tested the efficacy of the combination of EPA and DHA. Doses ranged from 0.2 to 4 g/day of EPA and from 0.3 to 1.4 g/day of DHA. To assess the level of depressive and depression-related symptoms, rather heterogeneous eval‎uation instruments were used (Hamilton Depression Rating Scale, Montgomery–Asberg Depression Rating Scale, Beck Depression Inventory, Childhood Depression Rating Scale, Childhood Depression Inventory, Edinburgh Postnatal Depression Scale, Geriatric Depression Scale, Hopkins Symptom Checklist Depression Scale, Postpartum Depression Screening Scale).

Three studies tested the combination of EPA and DHA in improving depressive symptoms in adolescents. Young et al. studied the benefits of 2 g/day of omega-3 fatty acid supplementation combined with individual–family psychoeducational psychotherapy (PEP) in comparison with PEP monotherapy, omega-3 fatty acid monotherapy, or placebo [84]. The authors showed that combined therapy could reduce behavioral symptoms, such as hyperactivity, impulsivity, and opposition that often appear with depression in young people. Similar results were obtained by Trebatická and colleagues [96] who enrolled depressed adolescents who were randomized to receive 2.4 g/day omega-3 (including 1 g EPA + 0.75 g DHA) or 2.467 g/day omega-6 (linoleic acid). They found a significant reduction in Children’s Depression Inventory (CDI) scores in the group receiving omega-3 [96]. Less encouraging findings were collected by Gabbay and collaborators [85] in patients who received EPA + DHA (2:1 ratio) versus placebo. The authors concluded that omega-3 fatty acids did not appear superior to placebo in adolescents with MDD.

Five studies [80,83,86,90,104] that eval‎uated the supplementation of omega-3 in adult patients suffering from unipolar depression showed that EPA and DHA were effective in reducing depressive symptoms [80,90], that subjects with MDD and a high number of inflammatory biomarkers had a better response to EPA compared to placebo and a lower response to DHA compared to placebo [83], that omega-3 fatty acid supplementation was superior to placebo in improving anxiety, sleep, and emotion regulation [86], and that 4 g/day of EPA can alleviate MDD in overweight individuals with elevated inflammatory markers [104]. On the other hand, three studies with similar characteristics [81,82,88] did not obtain statistically significant results in favor of omega-3 fatty acid intake.

Although some studies have yielded non-significant or unfavorable results, there is widespread agreement in considering omega-3 fatty acids as promising agents that can ameliorate depressive symptoms in MDD in combination with antidepressants or even in monotherapy [185,186]. A focal point to be considered is the difference in efficacy of the two fatty acids more commonly tested: EPA and DHA. Available evidence indicated that pure or predominant EPA, but not pure DHA, is effective in major depression [187].

To propose increasingly comprehensive treatments for major depression that also include new therapeutic agents, the neuromodulatory effects of the microbiome and its role in depression, anxiety, and stress responses have acquired great interest. In particular, the gut microbiota is suspected to affect brain functions and behavior through the gut–brain axis [13,188]. In the last ten years, thirteen trials have been performed to eval‎uate the impact of probiotics on depressive disorder [89,91,92,95,97,98,102,103,106,107,108,109,110]. Eleven studies showed encouraging results. Kazemi et al. [92] compared the effects of probiotics (Lactobacillus helveticus and Bifidobacterium longum) or galactooligosaccharides (GOS) with placebo and reported benefits in patients who received probiotics in terms of reduction of depressive symptoms (measured with BDI), while no significant effect was registered in the group that received GOS. Improvement of depressive symptoms in patients who received probiotics has also been found in other RCTs [91,102,103,106,109,110]. Moreover, probiotics also alleviated gastrointestinal symptoms [91], reduced IL6 blood levels [98], improved sleep quality [102,103,110], and reduced anxious symptoms [103,109,110]. Two RCTs [95,107] eval‎uated the efficacy of the probiotic Lactobacillus plantarum HEAL9 and of Lactobacillus helveticus Rosell®-52 plus Bifidobacterium longum Rosell®-175 with the addition of 200 mg/day of S-adenosylmethionine (SAMe). The authors found that these compounds improved depressive symptoms eval‎uated with the Zung Self-Rating Depression Scale (Z-SDS) [95], the Patient Health Questionnaire-9 (PHQ-9), and the HDRS (Hamilton Depression Rating Scale) [107]. Depressive symptoms also improved in patients with subthreshold depression [107]. Since the gut–brain microbiota axis is linked to depression and cognition, Schneider et al. investigated the effect of high-dose probiotic supplementation on the cognitive symptoms related to depression and highlighted the potential of microbiota-related regimens to treat cognitive symptoms of depression [108]. Less promising findings were reported in two other studies [89,97], which found no differences in cognitive functions between the group receiving probiotics and the control group.

Eight studies were conducted on vitamin D [87,93,94,99,100,101,105]. Low vitamin D levels seemed to be associated with a dysregulated hypothalamic–pituitary–adrenal (HPA) axis and depression. In many studies, the increased intake of vitamin D is reflected in increased serum concentration [93,94,99,101,105], but this is not always the case. In some studies, Vitamin D serum concentration did not significantly increase after supplementation [87,93,100]. This is probably due to the low dose of Vitamin D that was administered. RCTs that eval‎uated whether the increase in serum level of Vitamin D may improve psychiatric symptoms reported a reduction of depressive [94,99,105] and anxious symptoms [100].

Data of studies of MDD are summarized in Table 3.

4.4. Bipolar Disorder

Bipolar disorders (BDs) include bipolar I disorder and bipolar II disorder. They are characterized by recurrent episodes of major depression and hypomania or mania. In particular, the diagnosis of bipolar I disorder requires at least one manic episode that may have been preceded and may be followed by a hypomanic or major depressive episode. Bipolar II disorder is characterized by the lifetime experience of at least one episode of major depression and at least one hypomanic episode. Bipolar depressive episodes are approximately like major depressive episodes. Manic and hypomanic episodes are characterized by a marked change in mood (abnormally elevated, expansive, or irritable mood) and behavior during discrete periods. There are frequently and for varying lengths of time free gaps in between episodes. The most common initial presentation is depression and the age of onset is between 15 and 25 years. Early diagnosis and treatment are associated with a more favorable prognosis [189]. A growing number of investigations reported that inflammatory mechanisms may be considered mediators of pathophysiology in BDs [11,190] and that the omega-3/omega-6 fatty acid ratio, implicated in processes of inflammation, is often unbalanced in patients with BDs.

A cross-sectional study conducted by McNamara and collaborators [191] observed that the increased risk of developing bipolar disorder was associated with deficits in EPA and DHA levels in erythrocytes. The authors stated that low levels of omega-3 fatty acids can be considered a biomarker of prodromal risk for BD in young subjects. In light of this evidence, three recent studies, in which omega-3 was administered to young people at risk of developing bipolar disorder, found increased levels of omega-3 fatty acids in erythrocytes [120,126] and decreased functional connectivity of the amygdala with the right inferior temporal gyrus. These changes were associated with the reduction of the Childhood Depression Rating Scale–Revised score and the Clinical Global Impression-Severity Scale score [126].

To our knowledge, eight studies testing the effects of omega-3 fatty acids in patients with BD are available in the chosen time frame [112,113,118,122,124,127,129,130]. Daily dosages of omega-3 fatty acids ranged from approximately 650 mg to 2.25 g. One RCT suggested that the combined treatment with omega-3 fatty acids and inositol reduced symptoms of mania and depression in prepuberal children with mild to moderate bipolar spectrum disorders [113]. Another study suggested that the supplementation of omega-3 fatty acids improved mood variability, energy, irritability, and pain (measured using the Ecological Momentary Assessment scale) and reduced serum concentrations of inflammatory factors such as tumor necrosis factor (TNF-α), Interleukiyn-6 (IL-6), and highly sensitive C Reactive Protein (hs-CRP) [129]. Additionally, it was observed that omega-3 fatty acid intake can prevent relapse of bipolar depression [130] and reduce the severity of depression [129,130]. On the other hand, two studies did not confirm‎ these promising data. In the study performed by Mcphilemy et al. [122], in which 1 g of EPA plus 1 g of DHA was administered for 52 weeks in comparison with placebo, no differences were registered in the relapse rate of mood episodes and in the time to relapse. Moreover, the HDRS, the Clinical Global Impression (CGI), and the Global Assessment of Functioning (GAF) scores did not show significant changes [122]. Similarly, the RCT published by Saunders et al. [127] found no significant differences in the severity of mood symptoms between those who consumed a diet high in omega-3 (1.5 g/day) and low in omega-6 and a control diet standardized to the usual American distribution of 150 mg/day of omega-3 and a higher omega-6 content [127].

Three studies investigated the efficacy of the association of omega-3 fatty acids with psychotherapeutic interventions. Fristad and colleagues [112] compared the combination of psychoeducational intervention and 2000 mg/day of omega-3 fatty acids with placebo and active monitoring in youths with subsyndromal BD (BD not otherwise specified, cyclothymic disorder). Combined therapy was associated with greater improvement in depressive symptoms, but not in manic symptoms. However, all participants experienced and reported a decline in manic symptoms over the course of the study. The same research group [124] performed a follow-up study of 2–5 years after participation in the previous RCT to eval‎uate the long-lasting effects of combined therapy. The authors found that in participants, regardless of treatment group, manic symptom severity, executive functioning, and global functioning remained comparable to the end of the RCT. In addition, they found that those who persisted in supplementation with omega-3 fatty acids (it is not specified how long they did) had lower depressive symptom severity than those who discontinued treatment. The third study [118] aimed to assess the impact of 1870 mg/day of omega-3 fatty acid supplementation as a single treatment or in association with psychoeducational therapy on executive functions in youths with mood disorders (depressive disorder, cyclothymic disorder, or bipolar disorder not otherwise specified). Subjects receiving omega-3 fatty acid supplementation had a significant improvement in executive functions over time and the majority of patients reported concurrent improvements in dysphoric mood, irritability, and self-esteem [118].

Based on the promising results of probiotics on unipolar depression, their administration was also attempted in two studies including patients with bipolar disorders [116,125]. In a study dispensed Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12 in patients discharged after hospitalization for mania for 24 weeks. Probiotic supplementation was found to be associated with a lower rate of re-hospitalization [116]. In the study conducted by Sabouri et al. [125], BD symptoms were not investigated, but no changes in markers of blood inflammation and oxidative stress were observed after 8 weeks of probiotic therapy in patients with BD type 1 [125].

Three studies on vitamin supplementation were conducted in the period examined [114,123,131]. As vitamin D supplementation seems to improve symptoms of unipolar depression, Marsh et al. [114] administered 5000 IU/day of vitamin D for 12 weeks to patients suffering from BD and hypovitaminosis D, but did not find improvements in depressive, anxious, and manic symptoms measured with the Montgomery–Åsberg Depression Rating Scale (MADRS), the Hamilton Anxiety Rating Scale (HAM-A), and the Young Mania Rating Scale (YMRS). Furthermore, as vitamin B6, in addition to having an anti-inflammatory effect and reducing homocysteine, plays a role in serotonin and dopamine regulation, two studies were conducted on this agent. In the first study, [123] vitamin B6 (80 mg) was administered daily in BD patients during a manic episode with psychotic manifestations in association with lithium. No significant differences in mood were observed in patients compared to controls. On the contrary, in the RCT by Zandifar et al. [131] 66 patients were randomized to take, in addition to standard lithium treatment, 100 mg/day of vitamin B1, 40 mg/day of vitamin B6, or placebo, and it was found that vitamin B6, but not vitamin B1, improved mood compared to placebo and that both improved quality of sleep compared to placebo [131].

Extensive research in the pathophysiology of BD points to the existence of mitochondrial and bioenergetic dysfunction. So, the implementation of nutraceuticals with mitochondrial activity has received growing interest in the last few years. Three studies were focused on testing the effects of the mitochondrial modulators in BD: creatine monohydrate, coenzyme Q10, and N-acetylcysteine [117,119,121]. In an RCT with a placebo, creatine monohydrate was tested as an adjunctive therapy to the usual treatment for bipolar depression, with no significant effects on symptoms of the disorder [119]. Coenzyme Q10 (CoQ10) (a mitochondrial modulator, antioxidant, and anti-inflammatory agent) was found to be more efficacious in reducing depressive symptoms in patients with bipolar depression than placebo [117]. N-acetylcysteine (NAC), mitochondrial-enhancing nutraceuticals, or placebo were administered in a rather wide sample of patients suffering from BD. The authors observed that the participants with a better diet quality including N-acetylcysteine (Australian Recommended Food Score) reported a major decrease in subjective depressive symptoms and a greater clinician-rated improvement irrespective of treatment and time [121].

Given the potential effect of folic acid as an adjunctive therapy in major depression, this compound was also tested in one RCT in patients with BD. In the RCT by Sharpley et al. [111], folic acid (2.5 mg/day) or placebo was administered to boys at familial risk of developing BD. The authors demonstrated that the difference in the incidence of mood disorders in the two groups was not significant. However, in a post hoc analysis of this study examining the 18 participants who reached the primary endpoint, the median time to the onset of the mood disorder was 5 months in the placebo group and 15.5 months in the folate group. In a more recent open-label clinical study [115], L-methylfolate in combination with usual treatment was found to be efficacious in reducing symptoms of depression in BD, but controlled studies are needed to confirm‎ this initial evidence.

Data of studies of BD are summarized in Table 4.

4.5. Personality Disorders

The effect of omega-3 fatty acids and nutraceuticals in personality disorders has mainly been tested in patients with borderline personality disorder (BPD) and, unfortunately, there is no recent literature on this topic.

BPD is a widespread, long-lasting mental disorder characterized by impulsive-behavioral dyscontrol, unstable affective states, distorted self-image, and dysfunctional relationships.

The hybrid dimensional-categorical model of the DSM-5 describes personality disorders in terms of five personality domains: negative affectivity, antagonism, disinhibition, detachment, and psychoticism. In particular, BPD is diagnosed when traits belonging to the three domains of negative affectivity, antagonism, and disinhibition are present [192].

As several investigations showed a positive effect of omega-3 fatty acids on impulsive and aggressive symptoms in healthy and psychiatric subjects (suffering from Attention Deficit Hyperactivity Disorder, autism spectrum disorder, and bipolar disorder) [193,194,195], the efficacy of supplementation of these agents has also been tested in patients with BPD, who often show impulsive-behavioral dyscontrol and aggressive conducts.

To our knowledge, in the last ten years, there is only one RCT, lasting 12 weeks, in which 1.2 g/day of EPA and 0.6 g/day DHA were administered concomitantly with the usual valproic acid-based therapy or valproic acid as monotherapy in 43 patients with BPD. The study shows that the combined therapy improves symptoms, in particular regarding impulsive symptoms, behavioral dyscontrol, anger, and self-mutilating behavior [132]. Furthermore, there is a 6-month follow-up study of this RCT showing that improvement persists regarding anger outbursts [133].

In recent decades, it was found that omega-3 fatty acids were effective in reducing aggression and symptoms of depression when used without additional medications [196]. More recent studies suggested that these compounds were useful when used in combination with conventional pharmacotherapies to reduce depressive symptoms, impulsivity, self-harm, and anger outbursts [132,133].

Data of studies on BPD are summarized in Table 5.

The Cochrane systematic review focused on the pharmacological treatment of borderline personality disorder [197] suggested that, in addition to antipsychotics, mood stabilizers, and antidepressants, omega-3 fatty acids showed effects on anger, brief psychotic symptoms, and dissociative phenomena. However, a new edition of this review questioned the value of this evidence.

There are no data in the literature on other personality disorders, but one study showed that omega-3 fatty acid supplementation for a 6-month period is helpful in reducing aggressive and antisocial behaviors in a cohort of 324 children who had not received a specific psychiatric diagnosis, especially in females and those with psychopathic type personalities [134].

Regarding nutraceuticals, we found only scarce data on personality disorders or abnormal behaviors. A Korean study [15] found a close association between gut microbiota imbalance and facets of neuroticism (a heterogeneous trait consisting of multiple facets including anxiety, hostility, depression, self-consciousness, impulsivity, and vulnerability to stress). The study showed an inversely proportional correlation between anxiety vulnerability and the richness of the gut microbial flora: the greater these traits, the lower the richness of the microbiome. Furthermore, a significant difference was found between the low and high anxiety, self-awareness, impulsivity, and vulnerability groups. Specifically, patients with high anxiety and vulnerability had a low abundance of Christensenellaceae belonging to Firmicutes Clostridia, high self-awareness was correlated with a low abundance of Alistipes and Sudoligranulum, and impulsivity was correlated with a low abundance of Oscillospirales.

Some authors [13,198,199,200] highlighted a significant role in the etiology of BPD for early developmental processes, including prenatal stress and maternal dysbiosis, with effects mediated through the infant gut microbiome and its influence on amygdala development. The amygdala has an important role in the cortex and brain connectivity that may explain some of the abnormalities present in BPD, such as excessive activation of the amygdala towards negative emotions and reduced frontal regulation [201]. It is necessary to investigate whether the high levels of stress and dysphoria that are frequently associated with BPD mediate some of its consequences through gut dysbiosis and increased gut permeability.

Differences in the gut microbiome of BPD patients compared to controls were found in the Bacteroidetes/Firmicutes ratio (BFR), a marker widely used to detect alterations in gut microbial composition. In the sample, the BFR was higher in the BPD than in the control cohort, especially when controlled for BMI and depression. Furthermore, differences in the taxonomic composition of the gut microbiota were identified and revealed a potential dysbiosis among short-chain-fatty-acid-producing bacteria in BPD [202].

4.6. Reviews and Meta-Analysis

Over the last decade, several narrative reviews, systematic reviews, and meta-analyses have been carried out on nutraceuticals in psychiatric disorders.

The collected data suggested that EPA more than fatty acid composition may be effective in the early stages of schizophrenia and the chronic stages of the disorder, but the number of studies is still insufficient. More studies with standardized outcome measures, longer durations, and follow-up periods should be performed, as well as in samples at high risk for psychosis [22,23,26,27].

The efficacy of omega-3 fatty acids in autism spectrum disorders was not confirmed. Available findings are conflicting in their conclusions. Some reviews stated that no significant differences in the severity of autism symptoms were observed after omega-3 fatty acid treatment [162,163], except for lethargy, stereotypies, and hyperactivity [200]. However, a combination of omega-3 fatty acids and vitamin D produced some good effects on the social and behavioral outcomes of these patients [162].

Some meta-analyses showed positive results for EPA and DHA in monotherapy [185,186] and in combination with other drugs [185,203], particularly as an adjunctive therapy to antidepressants for moderate to severe major depressive disorder [203]. Nevertheless, some authors stated that the quality of the evidence was not good enough to determine the effectiveness of omega-3 fatty acids in the treatment of DDM [204,205,206,207,208]. The results indicated the therapeutic potential of EPA in depression at proportions ≥ 60% of the total composition EPA + DHA and doses ≥ 1 g/day and <2 g/day [187]. There is no evidence that the depressive symptoms that often occur during menopause are alleviated by omega-3 fatty acids [209].

In the systematic review [210] on nutraceutical supplementation in BDs, it was found that the adjunction of unsaturated fatty acids (mainly omega-3), folic acid, zinc, and CoQ10-probiotic to pharmacotherapy improved mood-related symptoms, while non-significant effects emerged from creatine, carnitine, vitamin D, inositol, or NAC.

Regarding personality disorders, a recent review [211] eval‎uated whether omega-3 fatty acids improved symptoms of borderline personality disorder. The most consistent results concerned affective dysregulation and impulsive behavioral dyscontrol.

Reviews that considered the tolerability of omega-3 fatty acids were concordant in maintaining these agents as safe and well tolerated in all psychiatric disorders, except for some episodes of diarrhea or dysgeusia [212].

Considering that dysbiosis is frequently discovered in patients with psychiatric disorders, probiotics and prebiotics have received considerable attention as potential psychiatric therapies. A systematic review [213] argued that limited inferences can be made regarding the efficacy of probiotics in schizophrenia and that the clinical utility of probiotics in this disorder has yet to be validated by future clinical trials.

As regards ASD, the Authors stated that despite promising preclinical results, prebiotics and probiotics have shown overall limited efficacy in the management of behavioral symptoms in children with ASD and that studies with standardized strains and fixed durations are needed [213]. Another review [214] and one meta-analysis [215] proposed approximately the same conclusions: probiotics and prebiotics did not significantly improve the severity of gastrointestinal abnormalities and psychopathology in ASD. On the other hand, a review [216] suggested the presence of changes in ASD symptoms and gastrointestinal symptoms after intervention with prebiotics, probiotics, and transplantation of fecal microbiota. However, the results should be taken with caution because there are very few studies that analyze the efficacy of long-term treatments and compare the different combinations of agents.

Most of the literature is concordant in maintaining that probiotics may have an antidepressant and anxiolytic effect, but the pooled effects were reduced by the paucity of trials with clinical samples [217,218,219,220,221,222,223,224,225,226]. A very recent meta-analysis supported probiotic implementation in pregnancy and breastfeeding women in order to prevent depressive and anxious symptoms [227]. In contrast, some reviews and meta-analyses [228,229,230] claimed that probiotic supplementation had an overall insignificant effect on mood and that interstudy discrepancies concerning probiotic dosage, bacterial strains, and strain combinations limited the comparability of clinical studies. Furthermore, most randomized trials were conducted in healthy individuals, making it difficult to extend findings to depressed patients.

The opportunity to explore the therapeutic potential of vitamin D supplementation in subjects with psychiatric disorders was sustained by several authors [231,232]. Neonatal vitamin D deficiency seems to be linked to an increased risk of schizophrenia. Also, patients with psychotic onset and stable schizophrenia have an increased risk of vitamin D deficiency compared to healthy controls [100,233], but these data have to be interpreted with caution as the reduced circulating vitamin D levels could be due to the poor general health and often unbalanced diet typical of patients with psychosis [233].

A meta-analysis [234] focused on maternal and neonatal vitamin D levels showed a trend of decreased early-life vitamin D concentration in patients with autism spectrum disorder and suggested that children with reduced maternal or neonatal vitamin D had a 54% higher likelihood of developing ASD. According to these analyses, vitamin D status could be related to the risk of ASD [234]. A maternal serum vitamin D level of more than 30 nmol/L was associated with lower odds of offspring with ASD [235]. Two reviews suggested that vitamin D supplementation is useful in MDD, especially in adults and in patients with a severe degree of depressive symptoms [236,237]. To our knowledge, there are no systematic reviews or meta-analyses about vitamin D supplementation in personality disorders.

The Canadian Network for Mood and Anxiety Treatment (CANMAT) guidelines (2022) concluded that among nutraceuticals with Grade A evidence, varying levels of support were found for adjunctive omega-3 fatty acids, vitamin D, adjunctive probiotics, adjunctive zinc, methylfolate, and adjunctive S-adenosylmethionine (SAMe) in the treatment of unipolar depression. Monotherapy with omega-3 fatty acids, folic acid, vitamin C, tryptophan, creatine, inositol, magnesium, NAC, and SAMe was not supported by sufficient evidence for this use. In bipolar disorder, omega-3 fatty acids had weak evidence of efficacy for bipolar depression, while NAC was not recommended. Vitamin D, NAC, and methylfolate were recommended to varying degrees in the treatment of the negative symptoms of schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for the prevention of transition to psychosis in high-risk youth with potential pre-existing fatty acid deficiency [238].

5. Conclusions

The present review investigates the use of omega-3 fatty acids and nutraceuticals in the treatment of psychiatric disorders, particularly schizophrenia, ASD, MDD, BD, and personality disorders. Our research predominantly focused on randomized controlled trials conducted in this field over the past decade.

Although the role of omega-3 fatty acids, particularly EPA and DHA, in psychiatric disorders has received growing interest in recent years and has been studied in an increasing number of clinical trials, there is a lack of general agreement on their efficacy and the available evidence is controversial and inconclusive. A major obstacle to drawing more definitive conclusions about the effects of these agents is the large heterogeneity among randomized trials. Differences in methods are notable and concern sample size, diagnostic criteria, type and doses of omega-3 fatty acids (e.g., EPA, DHA, or both, or the addition of omega-6, or omega-9 fatty acids), the association with standard drugs, duration of studies, and follow-up assessments.

The main evidence of the effectiveness of EPA and DHA was obtained in mood disorders. In particular, omega-3 supplementation has proven effective in reducing depressive symptoms in MDD and in BD, mostly in depressive but also in manic phases. Initial data on adolescent or older cohorts are promising, but further studies on larger samples are needed. Supplementation with a daily dose between 0.6 g and 4 g of omega-3 fatty acids has proven effective in reducing depressive symptoms in MDD and BD. We can also infer from follow-up studies, albeit sparse, that long-term treatments lead to more stable and persistent improvement in depressive symptoms.

Findings regarding schizophrenia and related psychotic disorders are still debated. In UHR subjects, the available evidence neither rejects nor supports the use of omega-3 fatty acids, while supplementation may be more effective in the early stages of schizophrenia and in the chronic stages of the disorder as an adjunct to antipsychotic treatment. It is possible to deduce that supplementation with a daily dose of 1–2 g of omega-3 fatty acids has a protective effect on the rate of conversion to psychosis and that omega-3 fatty acids have positive effects both on positive and negative symptoms of schizophrenia, as well as on the risk of relapse.

In ASD, the number of clinical trials and reviews has increased since our previous review [22,23,27], but a consensus among researchers has not yet been reached. The most favorable results concern the effect of high-dose omega-3 fatty acids in terms of reduction of hyperactivity, improvement of lethargy, and development of social interactions in children with ASD. As the most recent studies did not show important differences between the treatment groups, omega-3 fatty acid integration can only be proposed as a complement to other therapies in this clinical population.

In borderline personality disorder, the supplementation of omega-3 fatty acids has obtained favorable results on some core symptoms: impulsiveness, self-harm, and anger. Developments in this field are promising, but are still limited. Moreover, there are no new RCTs on omega-3 fatty acids compared to our previous reviews [22,23].

Most of the studies examined in this review agree on the improvements that omega-3 fatty acid integration produce from an inflammatory and metabolic point of view, both for preventive and therapeutic purposes.

Although the results are not sufficiently consistent, the available results on the effects of omega-3 fatty acids in different psychiatric disorders are promising in terms of clinical efficacy and good tolerability. The lack of significant adverse effects is a reason to consider the potential role of these agents, especially in the treatment of young or elderly individuals. Further investigations are needed to make more specific clinical objectives clear, to define the most appropriate modes of administration (doses, duration of treatment, omega-3 fatty acid molecules, and compositions), and to provide reliable guidelines for the use of these agents in clinical practice.

A more recent and constantly growing field of research is that of probiotics. The microbiome could regulate the immune system, maintain intestinal and blood–brain barrier integrity, and modulate the parasympathetic nervous system, brain function, and neuroinflammation. Understanding the regulatory mechanisms that govern microbiome–central nervous system interaction may help in understanding the pathological mechanisms that underlie several psychiatric and neurodevelopmental disorders, including depression and ASD. Results from human studies have shown that probiotics and microbial transplants can positively influence anxiety, stress responses, and depression, and can therefore help patients suffering from various pathologies.

There are no studies on probiotics in subjects at UHR for psychosis. Results about the efficacy of probiotics in the first psychotic episode are not conclusive, while in stable schizophrenia, they seem to be effective both from a symptomatic and a metabolic point of view. In ASD, studies show that probiotics improve both the characteristic symptoms of the disorder and the gastrointestinal dysfunctions. Regarding mood disorders, results are different in MDD and BD. In the majority of trials including patients with MDD, there was an improvement in depressive symptoms. In BD, a study showed a reduction in re-hospitalization rates after manic episodes, while other investigations found only poor improvement of symptoms.

Other molecules examined in this review have shown benefits, but their supplementation has not been tested in all disorders. For example, vitamin D showed some benefits in patients with schizophrenia and hypovitaminosis D; N-acetylcysteine was found to be efficacious in patients experiencing their first psychotic episode in terms of functional connectivity within the cingulate cortex; microbiota transfer therapy produced some effect in improving behavioral symptoms in ASD; folinic acid had unsatisfactory results in schizophrenia, while it appeared to improve symptoms of ASD; coenzyme Q10 had a beneficial effect in bipolar depression. It should also be noted that no studies on nutraceuticals are available in patients with personality disorders.

Designing and conducting such studies with higher levels of standardization and in larger cohorts represents a promising field of research that can be explored to help patients who do not respond to any of the traditional therapeutic regimens or who discontinued the usual therapies due to side effects or pharmaco-phobic traits.

Author Contributions

P.B.: conceptualization, methodology, writing—original draft preparation; R.N.: conceptualization, visualization, writing—original draft; C.M.: software, validation, visualization; P.R.: supervision; S.B.: conceptualization, methodology; writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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