Effects of Omega 3 Fatty Acids on Main Dimensions of Psychopathology

The usefulness of polyunsaturated fatty acids on inflammatory, cardiovascular, and the nervous system was studied in the last decades, but the mechanisms underlying their benefic properties are still partially unknown. These agents seem to express their action on the membrane phospholipid composition and permeability and modulation of second messenger cascades. In psychiatry, the efficacy and tolerability of omega-3 fatty acids were investigated in several psychiatric disorders, including major depression, bipolar disorder, personality disorders, high-risk conditions to develop psychosis, attention-deficit hyperactivity disorder, and autism spectrum disorders. Initial findings in this field are promising, and some relevant questions need to be addressed. In particular, the effects of these agents on the main symptom dimensions have to be investigated in a trans-diagnostic perspective. The present systematic review is aimed to examine the available data on the efficacy of omega-3 fatty acids on domains of psychotic symptoms, affective symptoms, impulsivity, and aggressiveness, and harmful behaviors, and suicide risk.


Introduction
In the last decades, the scientific literature has highlighted an urgent need to identify new compounds to treat psychiatric disorders in order to improve and boost available medications that entail not insignificant side effects. [1] As the harmful effects of the western diet, the absence of polyunsaturated fatty acids (PUFAs), on immune memory and inflammation processes are recognized [2], several studies evaluated the relationships between the low plasma level of long-chain polyunsaturated fatty acids and several medical conditions. [3] The effects of omega-3 fatty acids (n-3 PUFAs), including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), and of omega-6 fatty acids (n-6 PUFAs), including linoleic and arachidonic acid on overall human health have been extensively studied [4][5][6].
Nowadays, a consistent body of literature supports the importance of polyunsaturated fatty acids in brain function and the effect of their supplementation in mental disorders, but the molecular mechanisms underpinning their action are not completely clear [7][8][9]. Omega-3 fatty acids are essential fatty acids that humans and other animals require for good health, but cannot be synthesized. So, these compounds are introduced into the organism with food and metabolic conversion. The lipid derivatives of omega-3 PUFAs include anti-inflammatory eicosanoids, such as resins and resolvins, which mediate the effects on immune function [10,11]. Long-chain PUFAs, including at least 20 carbon atoms, have important functional roles as components of phospholipids forming the cell membranes [12], and as signaling molecules in all tissues, including the brain [13,14]. DHA is an essential omega-3 long-chain a central role [38]. So, n-3 PUFAs supplementation could have an effect in preventing transition to psychosis [39,40], in particular, in high-risk populations [41].
The symptoms dimension of psychosis is characterized by abnormalities in five symptom domains: delusions, hallucinations, disorganized thinking, disorganized behaviors, and negative symptoms. Lower levels of n-3 PUFAs seem to correlate with more severe negative symptoms in ultra-high risk (UHR) patients for psychosis and could be adopted as a biomarker that predicts the conversion to psychosis in UHR subjects [43].
Some findings suggested a role of EPA as an add-on therapy (in combination with antipsychotic therapy) in general, positive, negative, and depressive symptoms [46,47,[49][50][51] in patients with UHR and first episode of psychosis. EPA or DHA augmentation to antipsychotics reduced the deterioration of hippocampus tissues with a positive effect on negative symptoms [47], decreased the oxidative stress status of plasma with a positive effect on global and negative symptoms [50], and increased the telomerase levels in peripheral blood cells with a positive effect on the severity of illness [51].
Some authors suggested that in stable schizophrenia, omega-3 fatty acid supplementation had a beneficial effect on positive symptoms (delusions and hallucinations) [52,55]. Among PUFAs, EPA has been found superior than placebo and also than DHA in reducing positive [52,55] and negative symptoms [54]. Moreover, supplementation with EPA induced a less severe impairment of the course of psychosis [56].
Previous findings [62] showed that omega-3 fatty acids have beneficial effects on triglycerides in patients with psychotic symptoms and metabolic syndrome and may enhance the brain-derived neurotrophic factor (BDNF) levels through their anti-inflammatory properties with a reduction of cognitive dysfunction in these patients [63]. Probably, an appropriate dietary supplementation could play a partially therapeutic effect even in more severe patients, improving some behavioral aspects and reducing the cognitive deterioration [64]. In addition, EPA supplementation was found to be associated with a marked increase of glutathione, an antioxidant agent, in patients with first episode of psychosis. [46] Further studies are needed to investigate the role of omega-3 fatty acids as a treatment for the specific clusters of psychotic symptoms in psychiatric disorders other than schizophrenia. In fact, there is lack of evidence regarding the efficacy of PUFAs on the psychotic cluster of symptoms in bipolar disorder, schizoaffective disorder, and schizotypal personality disorder. To our knowledge only one case report documented the benefits of omega-3 fatty acids supplementation (EPA 1.187 g/day + DHA 0.613 g/day) in association with cholecalciferol (vitamin D3) and mood stabilizers for psychotic features in bipolar disorder [65].
In apparent contrast with the expectations, higher scores on positive schizotypal trait measures in healthy adults were found to be associated with higher concentrations of omega-6 and omega-3 fatty acids in red cell membranes [66]. These findings seem to support the hypothesis that high blood levels of PUFAs may confer some protection against psychotic breakdown [67].
Main findings are displayed in Table 1.

Affective Symptoms
Affective symptoms include depression, hypomania, mania, and anxiety symptoms. Abnormalities in affectivity characterize mood disorders but are also frequently associated with other mental disorders, such as psychotic and personality disorders. The role of PUFAs in treating affective symptoms such as depression can be linked to the inflammation hypothesis of the pathogenesis of depression and to the effects of EPA and DHA in reducing the effects of chronic activation of the inflammatory cascade [68]. In addition, it has been found that patients with major depressive disorder (MDD) have a lower level of EPA and DHA in their peripheral tissues (plasma, serum, and red blood cells) than control subjects [69].
The antidepressant efficacy of PUFAs could be partly explained by their role in myelinization processes-several models have been proposed to explain oligodendroglia cell loss/dysfunction in MDD. Increased levels of circulating corticosterone linked to the over-activation of the hypothalamic, pituitary, adrenal (HPA) axis in stress conditions could be at the origin of oligodendroglia loss/dysfunction in depression [70]. Studies in rats show that lower omega-3 PUFAs intake causes abnormalities of myelin [71] and that omega-3 PUFAs administration stimulates the expression of myelin proteins through the activation of signaling pathways involved in brain development [72]. Some experimental brain injury studies in rodents support this association and conclude that the supplementation with n-3 PUFAs increases the degree of differentiation of oligodendroglia cells [73,74].
Furthermore, an unbalanced omega-3/omega-6 ratio could lead to a range of functional consequences in the monoamine transport system [75]. In fact, there is evidence that severe n-3 PUFA deficiency alters the dopaminergic and serotonergic transmission systems, inducing an increased vulnerability to mood disorders. The mesolimbic dopaminergic pathway was more active, whereas the mesocortical pathway was found to be less active in rats with n-3 PUFA deficiency. This imbalance in dopaminergic neurotransmission could be related to symptoms of depressive episodes, such as lack of motivation, decreased response to reward, and impairment in intellective abilities [76].
The inflammatory response and the stimulation of BDNF have been hypothesized as two potential mechanisms through which omega-3 fatty acids could provide their anxiolytic effect. In particular, as anxiety is associated with an increased production of pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), the effect of n-3 PUFAs of decreasing inflammatory cytokines indirectly promote the reduction of anxious symptoms. Moreover, when BDNF is low, it fails to stimulate synaptic growth of serotonergic neurons in the brain, and low levels of serotonin are associated with anxiety. Thus, BDNF could reduce depression and anxiety by stimulating synaptic growth of serotonergic neurons in the brain [77,78].
With regard to anxious symptoms, observational and experimental studies have demonstrated that ω-3 supplementation could ameliorate anxiety symptoms. High ω-3 fatty acid intake is associated with reduced likelihood of meeting the diagnostic criteria for anxiety disorders [126,127] and lower levels of self-reported anxiety symptom severity [128,129]. However, the literature data on the efficacy of PUFAs on anxiety are still scarce and inconclusive. Two trials [130,131] suggested a positive effect of n-3 PUFAs (EPA 2.25 g/day + DHA 0.5 g/day) on anxiety in patients with substance abuse and one open-label study reported an improvement of anxious symptoms in patients with post-traumatic stress disorder [132].
Depressive and anxious symptoms often occur in patients with schizophrenia or other psychotic disorders. In particular, young people at UHR to develop psychosis who present affective symptoms (depression and anxiety) show lower plasma levels of omega-3 fatty acids and higher levels of omega-6 fatty acids then controls [41]. On this basis, some authors investigated the effects of EPA and DHA supplementation in patients with schizophrenia and depressive and anxious symptoms. The results showed that EPA at doses ranging between 1 and 4 g/day is efficacious in reducing the depressive symptoms [50,54] and anxious symptoms [54] of schizophrenia. Among personality disorders, n-3 PUFAs were found efficacious on depressive symptoms of patients with borderline personality disorder (BPD), both in monotherapy (EPA 1 g/day) [133] and in addition to standard pharmacotherapies (EPA 1.2 g/day + DHA 0.9 g/day) [134].
Main findings are displayed in Table 2.

Impulsive and Aggressive Symptoms
There is cross-sectional evidence that deficiency of omega-3 fatty acids is associated with hostility, aggressive behaviors, and impulsivity in both psychiatric and non-psychiatric populations [135]. The relationship between omega-3 PUFAs and aggression have also been explored in rodent studies, that have found an increase of aggressive behaviors with both omega-3 PUFAs deficiency [136] and high-omega-6 PUFAs intake [137]. Omega-3 administration seems to have beneficial effects in reducing aggression among the general population [138]. A study performed in a group of Australian inmates found that the n-3 PUFAs levels were inversely related to the degree of aggressive behavior and hostility [139]. The results of several studies collected in a meta-analysis [140] are encouraging for the use of omega-3 fatty acid supplementation to prevent and reduce aggressive behaviors in both children and adults. The relationship between abnormal PUFAs distribution and conditions characterized by a high-level of impulsivity could be partly explained by the effect of these compounds on the serotonin system and membrane stability. In particular, EPA influences serotonin release and DHA improves membrane-embedded serotonin receptor accessibility with an increase of cognitive function, propensity for prosocial behavior, and of impulsive behavior control [141].
Higher omega-6/omega-3 ratios have been found in subjects with anger, irritability, and aggressiveness, in particular during exposure to elevated inflammatory cytokines [142]. Thus, inflammation and inflammation-related genetic polymorphisms are two possible additional sources of variability that may contribute to understanding the biological substrates of aggressive states [143].
The relationship between omega-3 PUFAs and aggressive and impulsive behaviors have been observed in various psychiatric contexts. It is possible that omega-3 fatty acids may alter brain functionality prior to emergent or detectable behavioral changes [135].
Lower plasma levels of total omega-3 PUFAs and a trend toward a higher ratio of omega-6 to omega-3 PUFAs were observed in conditions with a high level of impulsivity. For example, among subjects with gambling disorder, a higher percentage composition of EPA and a lower AA/EPA ratio and AA/DHA ratio in the red blood cell membrane was observed in impulsive gamblers, compared with non-impulsive ones [144]. In a similar way, cocaine abusers with impulsive and aggressive behaviors showed an imbalance between omega-3 and omega-6 fatty acids [145,146], and violent males and impulsive offenders hospitalized in a forensic psychiatric unit presented a lower plasmatic DHA level than controls [147].
Some available evidence suggests a beneficial effect of omega-3 supplementation on aggressive and antisocial behavior in adolescence and adulthood [148]. The mechanisms underpinning these results is still unclear, although the upregulation of dysfunctional prefrontal regions is one candidate mediator [149,150].
Studies that evaluated the effects of PUFAs on impulsivity and aggressiveness in major psychiatric disorders indicated that the addition of rather low doses of omega-3 fatty acids (EPA 0.54 g/day + DHA 0.36 g/day) to antipsychotic treatment might reduce agitation and violent behaviors in inpatients with schizophrenia in the chronic phase [61]. Single therapy with omega -3 fatty acids (EPA 0.93 g/day + DHA 0.29 g/day) showed an improvement of impulsive dyscontrol and aggressiveness in patients affected by ADHD (attention deficit hyperactivity disorder) [151,152] and in patients affected by BPD [133,134]. Moreover, combined therapy with EPA (1-1.2 g/day) plus DHA (0.6-0.9 g/day) and valproic acid (800-1300 mg/day-plasma range: 50-100 µg/mL) was superior to single therapy with valproic acid on impulsive-behavioral dyscontrol and outbursts of anger in BPD patients [153]. Combined therapy with omega-3 fatty acids showed long-lasting effects at the end of 24 weeks of follow-up in terms of anger control [154].
Main findings are displayed in Table 3. Combined therapy with omega-3 fatty acids showed long-lasting effects after discontinuation in terms of anger control.

Self-harm Behaviors and Suicidal Conducts
Self-harm behaviors include self-injuries, such as cutting and self-mutilation, burning, scratching, or hitting body parts [155]. The desire to self-harm is a common symptom of some personality disorders, but is frequent also in patients with mood disorders, anxiety disorders, substance use disorders, eating disorders, post-traumatic stress disorder, and schizophrenia [156]. The classification challenge presented by repetitive, non-lethal, self-harm is reflected in the numerous terms used for it in the historical literature, including self-mutilation, focal suicide, parasuicide, suicide gesture, wrist-cutting syndrome, delicate self-cutting, deliberate self-harm, self-injury, and self-injurious behavior. Currently, DSM-5 [157] includes several types of repetitive, non-lethal self-injurious behaviors: nonsuicidal self-injury (NSSI), trichotillomania (hair-pulling disorder), excoriation (skin-picking) disorder, and suicidal behavior disorder.
A theoretical model indicates the pathways whereby cholesterol-lowering treatments could affect PUFAs and lipid rafts, leading to alterations in serotonergic neurotransmission, corticotrophic function, and inflammation, and thereby increase parasuicidal and suicidal risk. So, there could be a preventative intervention, with respect to suicide and parasuicide, in administering n-3 PUFA supplements to patients for whom lower cholesterol is medically important and who have or develop psychiatric vulnerabilities, for example, patients with cardiac diseases or metabolic syndrome [158,159].
Unfortunately, studies on the effect of PUFAs on self-harm behaviors and suicide are still sparse. Some of these were performed in subjects without a psychiatric diagnosis and showed that low n-3 PUFAs plasma levels were associated with an increased number of deaths for suicide compared with other causes of death in active duty US military personnel. Moreover, veterans treated with PUFAs reported a reduction in suicidal ideation after omega-3 fatty acid supplementation [160,161].
Other investigations found that low EPA and DHA percentages, elevated omega-6/omega-3 ratio, and higher AA concentration seem to be associated with increased self-harm and suicidal attempts in patients with mood disorders [162][163][164][165]. Having low levels of arachidonic acid and receiving a combination of high dose of EPA and lithium were found protective for suicide attempts and deliberate self-harm in the case of bipolar disorder [166].
In BPD patients, n-3 PUFAs supplementation (EPA 1-1.2 g/day + DHA 0.6-0.9 g/day), added to standard psychiatric therapies, showed a significant reduction of self-harming and parasuicidal attitudes [133,134,153,154]. In particular, the reduction of suicidal behaviors seems to be independent of change in the depression score [134].
Main findings are displayed in Table 4.

Conclusive Remarks
Recent evidence supports the importance of polyunsaturated fatty acids in brain functioning and the action of their supplementation in psychiatric disorders, but the underlying mechanisms of the potential preventive and therapeutic effect of PUFAs is still unclear.
Preclinical studies hypothesized that omega-3 fatty acids may attenuate stress-related changes in animals with depressive features, as well as in humans [167]. These agents seem to be involved in myelinization processes and synaptic pruning, that are fundamental processes during brain development. PUFAs have immune-modulatory, and anti-inflammatory properties through the modulation of omega-6 fatty acids and the promotion of resolvins, neuroprotective factors, and anti-inflammatory mediators. They are also involved in membrane fluidity producing an improvement of monoaminergic transmission.
In the last decades, the role of long-chain PUFAs in the treatment of several psychiatric disorders has gradually increased, as confirmed by the growing number of randomized controlled trials testing the efficacy of essential fatty acids, especially omega-3 supplementation. Nevertheless, an overall agreement about their efficacy is still lacking, and the results of most trials are controversial and inconclusive. Differences in methods, including sample size, selection criteria, choice, and dosage of fatty acids (i.e., EPA, or DHA, or a combination of the two), and the duration of supplementation, often make results not comparable.
The aim of this review is to evaluate, in a trans-diagnostic perspective, the efficacy of omega-3 fatty acids on the main psychiatric symptom dimensions, in particular on domains of psychotic symptoms, affective symptoms, impulsivity, and harmful behaviors.
Concerning psychosis, the available data on the effects of EPA and DHA needs to be replicated. However, initial findings are rather promising and show that these compounds, in addition to antipsychotics, may improve all symptom domains of psychosis, in particular negative symptoms. Evidence on the effects of PUFAs as single therapy for schizophrenic patients and on psychotic symptoms that are part of the clinical picture of psychiatric disorders other than schizophrenia are not sufficient.
The available literature reported promising data also on the role of n-3 PUFAs in the treatment of affective symptoms. In particular, these compounds, administered at high doses (1-2 g/day, with a ratio EPA:DHA = 2:1), seem able to improve depressive symptoms, both in monotherapy and in addition to antidepressants in major depression, in combination with mood stabilizers in bipolar depression, in addition to antipsychotics in schizophrenia. Evidence of the efficacy of manic symptoms is lacking, while the effects on anxiety need to be clarified and confirmed.
Concerning impulsivity and aggressiveness, the initial results on the beneficial effects of EPA and DHA supplementation are encouraging, both in single and combined interventions, and induce a decrease in the levels of impulsivity, outbursts of anger, and overt aggression. This area of psychopathology needs to be explored in depth by future investigations to allow us to draw more reliable conclusions. Another symptom domain that appears to be sensitive to the action of PUFAs is that of self-harm conduct. The effects of PUFAs were studied in patients with a high risk of harmful and suicidal behaviors, mainly in subjects with severe personality disorders, but also in patients with mood disorders. Additional important factors that require evaluation in this population include lipid-associated genetic variants and epigenetic markers that modulate the effects of lipid status and of PUFAs supplementation on self-harm and suicide risk.
In conclusion, polyunsaturated fatty acids are dietary supplements that can have a role on the basis of initial research data in treating several symptoms of psychiatric disorders, at least in combination with traditional medications. The lack of severe adverse effects is a significant reason to carefully consider the therapeutic potential of these agents. However, we have no sufficient evidence to draw final conclusions and to propose official indications for PUFAs in psychiatry. This is mainly due to serious limitations and considerable heterogeneity in the design and methods of available trials. As is suggested by the organization of this review, the authors' opinion is that less controversial and discordant data could be obtained in incoming studies by focusing, not on specific categorical diagnoses, but on psychopathological dimensions and symptom domains observed from a trans-nosographical perspective. Such dimensions could be the direct expression of the pathophysiological and biochemical pathways on which PUFAs actually produce their beneficial effects.
Funding: This research was supported by the funds of the Italian Ministry of Health for the Departments of Excellence.

Conflicts of Interest:
The authors declare no conflict of interest.