A Revision on the Effectiveness of Omega-3 Polyunsaturated Fatty Acids as Monotherapy in the Treatment of Major Depressive Disorder

Background Insufficient effectiveness and a difficult tolerability profile of antidepressant drugs for the treatment of major depressive disorder (MDD) have been reported, and polyunsaturated fatty acids (PUFAs) have been posited as reliable therapeutic alternatives. The present study investigated the efficacy of omega-3 PUFAs as monotherapy for MDD. Methods Two well-trained reviewers independently looked at the most significant randomized clinical trials (RCTs) from the PubMed database regarding PUFAs' employment in MDD compared to placebo; “major depressive disorder” and “omega-3 fatty acids,” or “omega-6 fatty acids,” or “polyunsaturated fatty acids (PUFA),” or “n − 3 polyunsaturated fatty acids,” or “eicosapentaenoic acid (EPA),” or “docosahexaenoic acid (DHA)” were used as the medical subject keywords. Results Of the initial 96 potential RCTs based on titles and abstracts, 82 studies did not meet the inclusion criteria and were excluded. Six studies were excluded from the remaining 14 after full text revision. Eight RCTs met all the inclusion/exclusion criteria without reporting clear evidence of PUFAs' effectiveness in the treatment of MDD. Conclusion At present, there is no opportunity to recommend the use of omega-3 PUFAs monotherapy for the treatment of MDD, although their supplementation may be useful in some specific populations.


Introduction
Major depressive disorder (MDD) represents a severe mental disease with a prevalence of about 10% of the world's population, which infuences general functioning and dayto-day life abilities. Several factors appear to contribute to MDD's heterogeneous etiological mechanisms [1][2][3]. Clinical research focused on defning efective treatments for both symptom improvement and prevention of recrudescence. Evidence has accumulated about efcacy of antidepressant drugs, in particular selective serotonin reuptake inhibitors (SSRIs), which nowadays is considered the frst-line treatment of major depressive disorders (MDDs), as reported by all the most important clinical guidelines [4]. To date, clinicians must address remaining unresolved needs in relation to MDD treatments, considering that too often insufcient efectiveness and a difcult tolerability profle of antidepressant drugs may lead to poor adherence to treatments [5]. Indeed, it is well known that these drugs produce a clinically relevant response in only 60% of patients who undergo complete pharmacotherapy as established by protocols [6]. Moreover, MDD pharmacotherapy often has an impact on patients' everyday life, entailing several side efects such as sexual dysfunctions, gastrointestinal disorders, nausea, vomiting, and cardiac problems [7]. For these reasons, such drugs are not always well tolerated, and patients have dropped out of treatment protocols at a rate of about 30% [8]. Several alternative options for treating major depressive and mood disorders have been posited, among which polyunsaturated fatty acids (PUFAs) have attracted the attention of clinicians and researchers. PUFAs are a group of fatty acids considered essential because they cannot be synthesized by the human organism; thus, they are acquired through diet [9]. Tese molecules have a double carbon bond on the atom from the methyl end carbon (omega carbon) of the acyl chain and, for this reason, are defned as polyunsaturated; depending on the location of the double bond, they are categorized as omega-3 or omega-6 fatty acids [10]. Te omega-3 fatty acids consist of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are derived from alpha-linolenic acid (ALA); seafood is considered the primary dietary source for these fatty acids, although they are also present in eggs, milk, plants, and vegetables [11]. On the other hand, plant oils such as sunfower, safower, and corn oils are the main source of linoleic acid (LA), which is the omega-6 precursor and can be further metabolized to other omega-6 fatty acids such as gamma-linolenic acid (GLA) and arachidonic acid (AA) [12]. Interestingly, AA can then be further converted into prostaglandins and leukotrienes, which are responsible for proinfammatory efects. In contrast, omega-3 fatty acids reduce the synthesis of the proinfammatory mediators by acting as competitive inhibitors to omega-6 fatty acids [13]. PUFAs are fundamental components of cellular membranes that are involved in several aspects of neurotransmission; as neurotransmitters are associated with synthesis, release, and metabolism, they appear relevant for neurodevelopment and neural functioning as well [14][15][16].
Evidence has accumulated about the role of PUFAs omega-3 and omega-6 in preventing and treating mood disorders such as MDD; indeed, populations with higher dietary fsh consumption showed lower rates of MDDs, as well as low rates of coronary disease mortality, cardiovascular disease mortality, stroke mortality, and general mortality [17,18]. An inverse relationship between fsh oil intake and the incidence of MDD has been previously described [19][20][21][22][23][24][25][26][27], and high seafood intake has been considered a protective factor against depressive episodes [28]. Consistent with these fndings, patients with mood disorders presented lower levels of omega-3 PUFAs in blood and brain tissue samples [29,30]. Similarly, low rates of DHA and total omega-3 PUFAs have been reported in postpartum depression [31], bipolar disorders were associated with low levels of DHA and AA [32] and anxiety disorders with low DHA and EPA as well [33]. Adult patients sufering from a major depressive disorder were reported to have lower omega-3 PUFA levels in their red blood cells and plasma [15]. Interestingly, a Cochrane study consisting of 25 randomized controlled trials, enrolling 1373 participants overall, assessed the efcacy of omega-3 fatty acids compared to placebo in major depressive disorder, with fndings about small to moderate efects in reducing depressive symptoms [34,35]. Te study noted the efcacy of omega-3 PUFA supplementation in the treatment of depressive symptoms appeared to be conditioned by the proportion of DHA and EPA rates: combinations mainly composed of EPA (EPA > 50%, 60%, and 80% of the dose, respectively) showed signifcantly greater efectiveness compared to combinations mainly composed of DHA (DHA > 50%, 60%, and 80% of the dose, respectively), regardless of the PUFAs' employment as monotherapy or adjunctive strategies [36].
Moreover, evidence states that dosages ranging from 720 mg/d to 1000 mg/d and PUFA combinations with EPA rates at proportion of 60% and above appear to determine more signifcant efectiveness in treating depressive symptoms [36].

Omega-3 Fatty Acids Mechanism of Action on Depressive
Symptoms. Although the exact biological mechanisms underlying the efcacy of omega-3 fatty acids (from now on, this term will be employed to refer to fatty acids clinically relevant in MDD treatment) in the treatment of depressive symptoms are still unclear, several hypotheses have been advanced. Omega-3 fatty acids take part in monoaminergic transmission regulation involving protein transcription; thus, low intake of omega-3 fatty acids entails lower levels of these fatty acids being present in the brain, along with an increased density of 5HT2 and D2 receptors in the frontal cortex [37][38][39][40][41][42]. A high intake of omega-3s is associated with serotoninergic metabolism, as already evidenced by the higher cerebrospinal fuid concentration of 5-hydroxy-indoleacetic acid (5-HIAA), which is a serotonin metabolite [17]. Moreover, the cerebrospinal concentration of 5-HIAA and somatotropin release appeared to increase with high omega-3 PUFA intake, in turn being associated with an improvement in depressive symptoms [43]. Te anti-infammatory capacity of omega-3 fatty acids has been suggested to explain their efect on MDD, which, in turn, is associated with an increase in proinfammatory markers [44]. Te therapeutic efect of omega-3 fatty acids might be related to their anti-infammatory and antioxidation activities, as already stated [45,46]. Oxidative stress has been associated with mood disorders [47] through the evidence of increased reactive oxygen species (ROS) levels [48,49]. Clinical improvements in patients with MDD seem to be favored by neuroplasticity and neurogenesis, as already stated, for therapeutic protocols involving antidepressants that appeared to increase neurogenesis in the hippocampus [50][51][52]. In addition, preclinical studies on animal models revealed that omega-3 fatty acids promote neurogenesis in the hippocampus [53][54][55] and play a role in neurotrophin modulation, likely mediating both neurogenesis and therapeutic efects [56][57][58].

Objectives
Although several studies have already addressed the efcacy of omega-3 and omega-6 fatty acids as adjunctive strategies to treat mood disorders and depressive symptoms, a lack of evidence emerges regarding the monotherapy employment of these fatty acids to treat major depressive disorders as an alternative to well-established therapeutic strategies according to international guidelines. Bearing this in mind, we sought to narratively review the literature to defne whether polyunsaturated fatty acids such as omega-3 and omega-6 are efective in monotherapy for major depressive disorders, representing a potential and reliable alternative to the current therapeutic protocols.

Materials and Methods
We conducted a literature review of the most signifcant studies regarding the implementation of monotherapy with omega-3 fatty acids in treating major depressive disorder. We surveyed the PubMed database, searching for randomized clinical trials (RCTs) published starting from January 1990 to January 2022 on the abovementioned subject. We employed the following medical subject keywords: "major depressive disorder" and "omega-3 fatty acids," or "omega-6 fatty acids," or "polyunsaturated fatty acids (PUFA)," or "n − 3 polyunsaturated fatty acids," or "eicosapentaenoic acid (EPA)," or "docosahexaenoic acid (DHA)." We subsequently looked at the most signifcant references from the abovementioned studies as well as relevant reviews and current controlled trials. We then included the most relevant randomized, double-blind, placebo-controlled studies (RCTs) that looked at the efcacy of omega-3 fatty acids as monotherapy for MDD in patients with an operationally diagnosed major depressive disorder according to DSM-IV or DSM-5 established criteria [59]. We excluded all studies that involved omega-3 fatty acids as add-on therapies, or that concerned samples characterized by nonspecifc or nonclinically assessed depressive symptoms, or that were implemented on other mood disorders such as bipolar disorders, or where study participants had other neuropsychiatric comorbidities, or studies that did not reach a signifcant statistical relevance.

Results
According to our inclusion criteria, we selected only studies of specifc randomized clinical trials that investigated the efcacy of omega-3 fatty acids as monotherapy for MDD. Of the initial 96 potential RCTs, we frst excluded 82 studies by reviewing the titles and abstracts. Of the remaining 14, we excluded 6 additional studies after two reviewers independently reviewed the full texts. Finally, 8 RCTs met all the inclusion/exclusion criteria (Table 1 and Figure 1).
Te frst study with this aim was conducted by Marangell et al. [60], who randomly assigned 35 patients with operationally diagnosed MDD to receive DHA 2 g/day or a placebo; patients were assessed by the Montgomery-Asberg depression rating scale (MADRS) [61] and the Hamilton depressive rating scale (HAM-D) [62]. Tey were enrolled with a score of MADRS >16 or HAM-D (28 items) >17, were not on psychotropic medication for at least two weeks, and were without neuropsychiatric or medical comorbidities. For a period of six weeks, 18 patients received DHA at a dose of 2 g/day, and 17 patients received placebo. Follow-up fndings did not show signifcant diferences between groups in regard to response rates, suggesting the absence of efectiveness of DHA monotherapy for adult outpatients with nonpsychotic major depression. Tis study represented the frst placebo-controlled study employing omega-3 fatty acids as monotherapy for the treatment of unipolar major depressive episodes.
In 2008, Freeman and colleagues [63] investigated the efcacy of omega-3 fatty acid administration in a population of women with perinatal MDD. Fifty-nine women were randomized to 1.9 g/day EPA/DHA or placebo for eight weeks. Scores on the HAM-D and the Edinburgh postnatal depression scale (EPDS) [64] both showed a signifcant decrease for all groups, although some or no dose-related efect was observed.
A randomized control trial (RCT) was conducted by Su et al. in 2008 [65], comparing omega-3 fatty acids (3.4 g/d) with placebo in 36 pregnant women with a diagnosis of MDD assessed by the HAM-D and as secondary measures through the EPDS and the Beck Depression Inventory (BDI) [66]. After 8 weeks, subjects in the omega-3 group had signifcantly lower HAM-D scores and depressive symptoms, showing that omega-3 fatty acids may have therapeutic benefts in treating depression during pregnancy.
However, the opposite results appeared in a study conducted in the same year in women with major depression during the perinatal period. Twenty-six subjects were recruited and received either fsh oil or a placebo for six weeks. Te results suggested that there was no beneft for omega-3 fatty acids over placebo in treating MDD during the perinatal period [67].
Jazayeri et al. [68] sought to compare the therapeutic efects of EPA, fuoxetine, and their combination in MDD. Sixty outpatients who had received the diagnosis of MDD based on DSM-IV criteria and who had scored >15 in the 17item HAM-D were randomly assigned to receive either EPA (1 g) or fuoxetine (20 mg) or their combination daily for 8 weeks. Te combination of EPA and fuoxetine was signifcantly more efective than the administration of only EPA or fuoxetine from the fourth week of treatment; fuoxetine and EPA appeared to be equally efective in improving depressive symptoms, with response rates (>50% decrease in baseline HAM-D) of 50%, 56%, and 81%, respectively, in the fuoxetine, EPA, and combination groups. A synergistic interaction between EPA and fuoxetine was somehow suggested.
In 2015, Mischoulon et al. [69] compared the efcacy of EPA and DHA as monotherapies for MDD by implementing a 2-site, placebo-controlled, randomized, double-blind clinical trial. One hundred and ninety-six participants with a diagnosis of MDD based on DSM-IV criteria and with a baseline score at the HAM-D-17 of ≥ 15 were initially enrolled, but only 154 participants completed the program. Participants were randomly assigned to receive an oral treatment with oral EPA-enrichedn − 3 1000 mg/d, DHAenrichedn − 3 1000 mg/d, or a placebo for 8 weeks. All the recruited groups showed signifcant improvement in depressive symptoms as evaluated by the outcome measures (the HAM-D-17, the 16-Item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR-16) [70], and the Clinical Global Impression-Severity scale (CGI-S) [71]), but no signifcant diferences were found between groups receiving omega-3 fatty acids and the placebo group. Response and remission rates for recruited groups were 40%-50% and 30%, respectively, but no signifcant diferences between them were observed. Neither EPA-enriched nor DHAenriched combinations appeared signifcantly more efective than a placebo for the MDD treatment.
International Journal of Clinical Practice  Chang et al. [72] sought to investigate the efcacy of omega-3 fatty acids for the treatment of MDD in a population of individuals with cardiovascular comorbidity. Fifty-nine patients were randomly assigned to receive either omega-3 fatty acids (2 g per day of eicosapentaenoic acid, EPA, and 1 g of DHA) or a placebo for 12 weeks. Tey underwent an assessment based on the HAM-D, the BDI, the electrocardiogram, and the blood biochemistry, both at baseline and endpoint. Te authors did not observe any signifcant diference between groups concerning depressive symptom improvement as described by the psychometric scores. However, once stratifed for depression severity, the omega-3 fatty acid supplementation appeared to improve core depression symptoms [73] in the very severe MDD group [72].
Gabbay et al. sought to investigate the efcacy of the employment of omega-3 fatty acids as monotherapy for MDD in a sample of adolescents. Tey found that omega-3 fatty acids did not lead to signifcant improvement compared to placebo regarding any clinical feature of MDD, including symptoms' severity, levels of anhedonia, irritability, and suicidality. No signifcant diferences resulted between groups in terms of response rates either [74].

Discussion
Starting from the literature that was accumulated about the minimal evidence of omega-3 fatty acid efcacy as reliable treatments for mood disorders and depressive symptoms, we decided to strictly include in our review design only fndings based on studies that considered omega-3 fatty acids as monotherapy for major depressive disorder. We aimed to shed light on these relatively new treatment strategies, questioning whether to consider them reliable alternatives to common antidepressant drugs in the framework of MDD treatment approaches. To our knowledge, the present narrative review represents the frst attempt to recognize and collect the most relevant evidence reported in the literature about the abovementioned clinical question. What emerges from our review is the lack of clear evidence of the efcacy of omega-3 fatty acids employment as monotherapy for MDD, considering the contradictory nature of reported fndings. Indeed, studies do not seem to reach a common agreement over the opportunity of fatty acids' clinical employment for such a severe mental illness as major depressive disorder, and most of the efects of their administration were reduced once publication bias was corrected. However, it is important to note that several methodological issues may have afected previous studies and should be addressed to clarify such clinical hypotheses: studies have varied concerning specifc omega-3 fatty acids employed, sample sizes, duration of therapies, posology of administered combinations, and the employment of omega-3 fatty acids as monotherapy or adjunctive therapies [75]. Although all the recruited studies met the established inclusion criteria, diferent variables have been considered, such as the studied populations, the psychometric rating scales that have been employed, and the administered formulations and dosages of omega-3 fatty acids. For instance, we observed that the use of omega-3 fatty acids in monotherapy for MDD appeared to be signifcantly efective in special populations such as women with perinatal MDD [63], pregnant women [65], and individuals with cardiovascular comorbidity and severe MDD [72]. Other diferences in study designs are nested in the drug combinations or formulations that have been employed; for example, Jazayeri et al. [68] have focused on the synergistic interaction between omega-3 fatty acids and fuoxetine.
A search through the leading medical databases led to the selection of 96 potential RCTs.
Te titles and the abstracts of the selected RCTs were surveyed.
Two well-trained reviewers independently examines the full texts of the remaining 14 RCTs.
8 RCTs met all the inclusion/exclusion criteria and were defnitively selected.
82 RCTs were of topic and therefore excluded.
6 RCTs did not meet the inclusion criteria and were consequently excluted.

International Journal of Clinical Practice
Tus far, no common agreement about dosage and duration of omega-3 fatty acid administration has been reached to demonstrate their potential efcacy in MDD treatment, although 1 g/day of EPA or combinations mainly composed of EPA demonstrated higher efcacy than combinations mainly composed of DHA, consistent with previous literature [36]. Te fact that specifc combinations of fatty acids such as EPA and DHA might difer in their efectiveness in treating MDD should warrant greater attention from clinical researchers.
Our fndings seem partially consistent with those suggesting that omega-3 combinations mainly composed of EPA appear more efective, both in monotherapies and adjunctive treatment strategies. In this regard, concerning the higher efectiveness of the 2 : 1 ratio EPA/DHA formulation, only Su et al. [65] reported a signifcant improvement in depressive symptoms in a population of women with MDD. Te other two studies employing a 2 : 1 ratio EPA/DHA formulation [72,74] did not confrm such results. It is worth noting that the last two studies were conducted in special populations, such as adolescents and patients with cardiovascular comorbidities (Table 1). Moreover, these studies used diferent psychometric rating scales to investigate specifc clinical dimensions. Su et al. used the HDRS, EPDS, and BDI scales, which are particularly focused on categorical depressive symptoms, whilst Gabbay et al. employed the CDRS-R scale, a tool tailored to children and adolescent populations, and the CGI scale, focusing on symptoms' severity outcomes. Terefore, it cannot be ruled out that these diferent study designs may have afected the results and that heterogeneity in omega-3 combinations may have led to contradictory fndings with regard to their efectiveness. In the present review, we sought to accurately describe the diferent omega-3 combinations employed in the recruited RCTs (Table 1). Terefore, considering our fndings, we did not report clear recommendations about the employment of specifc omega-3 combinations as monotherapy for MDD, but, as previously mentioned, other studies are required to shed light on this topic. Bearing this in mind, it should be noted that the trial conducted by Marangell et al. [60] involved a treatment intervention with only DHA and not EPA or other omega-3 fatty acids, likely leading to conditioning fndings. Other methodological concerns may have infuenced previous clinical fndings, such as the lack of coherence in the diagnosis and the criteria defnition to enroll participants who would have been assessed. In order to address this aspect, we sought to limit our review to RCTs and studies that recruited people operationally diagnosed with major depressive disorders, according to DSM-IV or DSM-5 criteria. Terefore, we should notice that the study conducted by Tajalizadekhoob et al. [76] was implemented on a sample of elderly individuals whose depressive symptoms were assessed through the scoring of the Geriatric Depression Scale-15 (GDS-15) [77] and not based on operational criteria. Moreover, from this study, it appears that participants' depression was signifcantly improved by omega-3 fatty acids intake when patients were not under antidepressant therapy, likely indicating a less severe degree of depression.
Indeed, no signifcant diferences in GDS-15 appeared between groups when considering participants taking antidepressant drugs: the efect of omega-3 on depressive symptoms of elderly people may be partially explained by the average low intake of fatty acids due to the poor diet this population is exposed to.
A larger efect of fatty acids in samples of individuals taking antidepressant drugs has been observed, likely suggesting a synergistic efect between them and omega-3 fatty acids [68,78]. It has been posited that fatty acids may biologically modulate both the interaction between neuronal membranes and antidepressants and the infammatory pathways activated in depressive states [78][79][80][81]. Other potential mechanisms concern the evidence for omega-3 fatty acids' role on serotonergic neurotransmission [82] and the p-glycoprotein mediated enhancement of antidepressant transport across the blood-brain barrier [83].
Overall, fndings from selected studies showed a lack of clear evidence for the efcacy of the employment of omega-3 fatty acids as monotherapy for MDD, despite some empirical use and biological evidence, a hypothesis that is corroborated by relevant meta-analyses and systematic reviews involving both studies that used omega-3 fatty acids in monotherapy and in augmentation treatment. In 2012, Bloch and Hannestad [35] conducted a meta-analysis involving 13 RCTs on 731 participants with the aim of comparing omega-3 fatty acids to placebo in patients with moderate or mild depressive symptoms at baseline. In 7 RCTs, omega-3s were used as monotherapy, and in 6 RCTs, they were used as an augmentation treatment. Tey found a small, nonsignifcant beneft of omega-3 fatty acids for the treatment of MDD. Tis meta-analysis included studies involving self-rating scales instead of diagnostic and structured interviews, likely afecting results. Interestingly, another meta-analysis conducted by Yang et al. in 2015 [84] reviewed 8 RCTs involving 367 participants receiving a combination of DHA and EPA compared to a placebo for the short-course treatment of depression in women: 6 RCTs investigated the efcacy of the combination administered as monotherapy and 2 RCTs as augmentation therapy. Te authors found that the combination of EPA and DHA appeared to show a benefcial efect on depressed mood in women with MDD compared with placebo. It should be noted that the heterogeneity of the trial designs that have been incorporated into the main meta-analyses may partially explain their contradictory fndings. Tese studies often involved RCTs investigating the efectiveness of omega-3 fatty acids in augmentation strategies and not in monotherapy or including subthreshold depressive symptoms without meeting criteria for a MDD diagnosis. However, in a recent review [85], the expert consensus of the International Society for Nutritional Psychiatry Research (ISNPR) suggested the use of omega-3 PUFAs for the treatment of MDD in specifc patient subgroups like pregnant women, children, and the elderly. Interestingly, it has been suggested that in adolescents and young adults, the use of omega-3 fatty acids for MDD treatment may represent a reliable strategy likely to avoid major side efects of traditional drugs [85]. Although patients afected by MDD at diferent ages may show specifc symptoms, it has been reported that the efcacy of omega-3 fatty acids does not appear to vary with regard to the age of the recruited samples [86]. Te employment of omega-3 fatty acids for prevention in populations at high risk for depression has been suggested as well. Moreover, omega-3 fatty acid efcacy has been reported in populations of patients with depressive disorders and medical comorbidities such as cardiovascular, infammatory, and metabolic diseases; it may be suggested that the well-establishedanti-infammatory activities of omega-3 fatty acids would play a relevant role in this respect, likely reducing infammatory factors, which in their turn appear associated with depression [15,72,87]. Some authors suggested a role for diets with low omega-3 fatty acid intake in increasing the risk of the development of depressive symptoms in high-risk populations [69]. Indeed, the fndings that support the strength of omega-3 fatty acids efcacy in MDD treatment have appeared to decrease according to more recent studies in the literature where the latter have been implemented in samples and populations adopting increasingly balanced diets with already higher omega-3 fatty acids intake compared to the past. Tis factor likely infuenced fndings, and both the relevant confounders' variables and the socioeconomical background should be addressed in order to arrive at a valid assessment of the omega-3 fatty acids efcacy. For example, as already reported, the association of low fsh intake with an increased incidence of mood disorders was the primary reason to investigate the efcacy of omega-3 fatty acids in the treatment of these mental illnesses, thus suggesting a confounding role for the basic economic status with which diet likely appears associated [88]. Similarly, higher efcacy of omega-3 fatty acids was associated with studies, with high heterogeneity likely infuencing the efect sizes to the detriment of the real efcacy of omega-3 fatty acids [35]. To note, the tolerability of omega-3 fatty acids has been previously established, and their administration has been associated with few impairing side efects such as fshy belching, fatulence, and diarrhea. However, unclear evidence about long-term administration efects has been provided given the evidence of omega-3 fatty acids' predisposition to oxidative degradation, which may potentially represent a late adverse efect [89]. More studies are required in this feld.

Conclusions
We reviewed the most relevant RCTs investigating the employment of omega-3 fatty acids as monotherapy in MDD treatment, and we did not fnd any clear evidence of efcacy for such therapeutic strategies. Bearing our fndings in mind, we suggest that the use of omega-3 PUFAs as a monotherapy for the treatment of MDD is not yet supported by signifcant evidence of efectiveness, and more studies are likely required to shed light on this topic. However, omega-3 fatty acids supplementation or a diet rich in omega-3, thanks to their quite safe profle, may be suggested in some specifc populations to prevent or reduce depressive symptoms. Overall, the therapeutic efect of omega-3 fatty acids in major depressive disorder is lacking, and, to date, opportunity costs and inefectiveness do not allow for their consideration as a valid alternative in treatment programs.

Data Availability
Te data that used to support the fndings of this study are available from the corresponding author upon request.

Conflicts of Interest
Te authors declare that they have no conficts of interest.