The Promising Use of Omega-3 Supplementation in Psychiatric Diagnoses

Abstract

It has been evident that the past few years of the COVID-19 pandemic have challenged many people physically, emotionally, and most of all, psychologically; the increase in prevalence of mental health diagnoses and associated symptoms has resulted in an immense need for integrative mental health management tools due to the numerous side effects of conventional medication, suboptimal reduction of symptoms, and the reluctance of parents to give children conventional medication. Omega-3 polyunsaturated fatty acids (PUFAs) have been effective at alleviating symptoms in various neurological, cardiovascular, and endocrine diagnoses, and more due to their anti-inflammatory nature. Omega-3s are an excellent candidate for therapy in psychiatric diagnoses due to their moderate to high efficacy and lower level of side effects. The goal of this article is to comment on the best dosages, durations, and symptom profiles that have resulted in clinical improvement for schizophrenia, major depressive disorder (MDD), bipolar disorder (BD), and attention deficit hyperactivity disorder (ADHD). This article also highlights mechanisms of action that are relevant and that underlie the utilization of omega-3 PUFAs in a clinical setting, either alone or as an adjunct therapy.

Introduction

It has been evident that the past few years of the COVID-19 pandemic have challenged many people physically, emotionally, and most of all, psychologically; hence, the trend of an increase in psychiatric disease has resulted in a greater need for efficacious therapy. Alongside this is the notion that psychiatric diagnoses can be challenging to treat. While antipsychotic and antidepressant medications are aimed at alleviating psychotic and affective symptoms, the effects are often suboptimal, and come with many unwanted side effects. There seems to be a growing need to supplement conventional treatment with naturopathic options in this group of disorders. Some people are also wary of administering medication to their children (i.e. for ADHD). Given these needs and constraints, there has been an increasing interest and recent research on omega-3 supplementation in psychiatric disorders. The objective of this article is to review effects of omega-3 supplementation on schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder, and depression.

Associated Mechanisms of Action of Omega-3s in Psychiatric Diagnoses

The average human has an Omega-3 Index (O3I) – a major of EPA and DHA in red blood cell membranes – between two and 20%; an optimal level is said to be eight to 11%, whereby a decreased O3I is associated with an increased risk of psychiatric diagnoses (von Schacky 2021). It is thought that increasing this index via omega-3 polyunsaturated fatty acid (N-3 PUFA) supplementation may confer neuroprotective effects. Several studies have shown that an accumulation of N-3 PUFAs in neural cells may have a positive effect on neuronal function, alongside anti-inflammatory and antioxidant activities (Itua and Naderali 2010, Orr et al 2013). Other activities of N-3 PUFAs include increasing membrane fluidity (Meijerink et al 2013), activating peroxisome proliferator activated receptors, and enhancing neurotrophic support (Kou et al 2008). These multi-faceted mechanisms of action lend support for theories of possible neuroprotective and cognitive benefits in psychiatric disorders.

Overall, collective expertise on the subject has concluded that PUFAs and their mediators carry out the following processes in the central nervous system:

(1) the maintenance of cell structure and function of neurons, glial cells, and endothelial cells,

(2) the modulation of neuro-inflammatory processes and associated biomarkers in blood, and

(3) the regulation of neurotransmission (Bazinet and Layé 2014).

These mechanisms give clarity on the underlying mechanisms of why omega-3s have an impact on mood regulation, symptom control, and cognitive function. This further elucidates how N-3 PUFAs may be a novel and efficacious agent for an array of psychiatric disorders such as depression, bipolar disease, ADHD, and schizophrenia.

1. Molecular Findings for Major Depressive Disorder and Bipolar Disorder

It is thought that decreased levels of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are one of the causes of certain psychiatric disorders. One meta-analysis of 14 case-control studies showed significant reductions in EPA and DHA in plasma and erythrocytes in subjects with major depression (Lin et al 2010). Another set of studies showed that bipolar patients had significant erythrocyte DHA and/or EPA deficits when cross-comparing them to healthy counterparts (Chiu et al 2003, McNamara et al 2015). The protective function of N-3 PUFAs was examined in patients with BD. DHA and EPA caused increased membrane fluidity, as detected by reductions in a membrane integrity marker T2 values, compared to controls in a four-week study (Hirashima et al 2004). Cross-sectional studies have found that children with a very high risk for mood disorders had erythrocyte EPA and DHA deficits compared with healthy individuals (Clayton et al 2008). Plasma EPA and DHA deficits were also confirmed in those with major depression alongside comorbid anxiety disorders (Liu et al 2013).

• Molecular Findings for Schizophrenia

Parletta and colleagues found that blood levels of EPA and DHA were reduced in those patients with schizophrenia and depression (Parletta et al 2016). One study showed that those who had taken no medication at the onset of psychosis had erythrocyte DHA and arachidonic acid (AA) deficits compared with healthy individuals (Khan et al 2002). An interesting meta-analysis of 18 case-control studies also showed significantly low levels of DHA and AA in schizophrenic individuals (Hoen et al 2013). These studies have suggested that deficits in erythrocyte DHA and AA may predispose patients to, and persist in those diagnosed with, psychosis.

• Molecular Findings for Attention Deficit Hyperactivity Disorder

This same logic was used in another meta-analysis of nine cross-sectional studies that found lower blood EPA and DHA levels in children with ADHD compared with healthy controls (Hawkey and Nigg 2014). The rationale behind the use of omega-3 supplementation was an intent to reduce symptoms on a clinical level and correct this deficiency on a molecular level.

Support For the Use of Omega-3s in Schizophrenia

A growing body of evidence exists for the use of omega-3s in schizophrenia, mostly as an adjunct therapy but also alone. One recent randomized, double-blind, placebo-controlled trial (RDBPCT) demonstrated excellent therapeutic potential. Fifty schizophrenia inpatients with a score of >4 on the Modified Overt Aggression Scale (MOAS) who took antipsychotics also received omega 3s (540/360mg EPA/DHA) (N=28) or placebo (N=22) for 12 weeks; MOAS scores (i.e. violence) of participants in the fish oil group declined significantly compared to the placebo group (t=-2.40, P <0.05) (Qiao et al 2018). A short set of studies suggested that when any dose of omega-3 ethyl-EPA (E-EPA or EPA) was compared with placebo, the need for neuroleptic medication seemed to have been decreased for people that took omega-3 (n=30, 1 RCT, RR 0.73 CI 0.54 to 1.00) and mental state likely improved (n=30, 1 RCT, RR not gaining 25% change in PANSS scores 0.54 CI 0.30 to 0.96, NNT3 CI 2-29) (Joy et al 2000).

A Cochrane Review examined the use of omega-3 and evening primrose oil to treat symptoms of schizophrenia. The review found positive findings of EPA versus placebo for scale-derived mental state outcomes; thus, improved symptoms. It should be noted that the data were preliminary and further studies with more power are needed to confirm the effect to a greater degree. A smaller study within this review looked at using EPA as the only treatment for people hospitalised for relapse. The results showed that EPA may have helped 33% of people avoid using antipsychotic medication for 12 weeks (RR 0.6, CI 0.4-0.91) (Joy et al 2000).

One meta-analysis showed that when individuals in the prodromal state of schizophrenia took omega-3, it reduced psychotic symptom severity and lowered conversion rates to first-episode psychosis. Similar findings were echoed with first-episode schizophrenia; omega-3 lowered non-psychotic symptoms, required smaller antipsychotic medication dosages, and heightened early treatment response rates (Chen et al 2015). One RDBPCT provided clinical value by mention of dosage; 2200mg of N-3 PUFAs or placebo was given for 26 weeks, and the study evaluated symptoms via first-episode schizophrenia. The authors concluded that this dosage was effective as an adjunctive therapy as per the following results: improvement of 50% in symptom severity (p=0.017), an improvement in depressive symptoms (p=0.006), and a higher level of functioning (p=0.01) in the N-3 PUFA group (Pawełczyk et al 2016).

Support For the Use of Omega-3 in Bipolar Disorder and Depression

N-3 PUFAs are thought to be involved in the pathophysiology, treatment, and prevention of bipolar disease (BD) (Sublette et al 2011). A small DBPCT examined the effects of EPA treatment in BD patients as associated with increased brain levels of N-acetyl aspartate (NAA), a marker thought to be active in neuronal integrity. Fourteen female BD patients were given 2g of E-EPA or placebo each day for 12 weeks. The results showed a significant rise in NAA levels in the E-EPA group versus placebo (p=0.027), thus establishing grounds for a possible neuroprotective role of N-3 PUFAs in BD that can be corroborated with larger studies (Frangou et al 2007). Several meta-analyses, such as this one, confirmed that omega-3 use as an adjunct therapy in BD helped to reduce the depressive, but not manic symptoms, likely signalling that further research may be needed for a broader scope of symptom analysis (Sarris et al 2012).

A recent study by Li et al confirmed that supplementing with omega-3s for 12 weeks increased blood EPA/DHA levels in depressive patients versus placebo (Li et al 2021). Omega-3 PUFAs have also been proposed to have a beneficial effect when used alongside conventional medication in major depressive disorder (MDD). A meta-analysis demonstrated a beneficial effect of omega-3 PUFAs on depressive symptoms in MDD (standardized mean difference = 0.398 (0.114-0.682), P=0.006); the statistics showed a positive correlation between increasing the EPA dose and positive effects on MDD symptoms. EPA was also shown to provide better outcomes in patients taking antidepressants than in those who were taking EPA alone (Mocking et al 2016).

Support For the Use of Omega-3 in ADHD

N-3 PUFAs were also proposed to be useful in the treatment of ADHD. A randomized control trial with supplementation of 500mg per day of EPA and 2.7mg per day of DHA reduced inattentiveness but not hyperactivity (Gustafsson et al 2010). Another study showed that in youth, as measured by parent-rated input, there were decreased symptoms of hyperactivity, inattentiveness, and impulsive behaviour in the treatment group (Sinn et al 2008). One meta-analysis showed that in the primary analyses, N-3 PUFAs did not show improvements in emotional lability (EL), oppositional behaviour, conduct problems, or aggression. However, subgroup analyses of higher quality studies and those meeting strict inclusion criteria found a significant reduction in EL and oppositional behaviour with N-3 PUFA supplementation. This could indicate that larger sample sizes may amplify this effect and show value in highlighting the effects of N-3 PUFAs on reducing EL in subsets of children with ADHD (Cooper et al 2016). A randomized controlled trial showed that supplementation with N-3 PUFAs improved the red blood cell fatty acid profile by significantly reducing AA/DHA in the intervention group when compared with controls (P=0.000) in children with ADHD (Wu et al 2015).

Evidence for omega-3 as an adjunct therapy was shown in an interesting study where individuals (N=90) were randomized to omega-3/6, long-acting Methylphenidate (MPH), or both for one year; ADHD symptoms, as shown by the Clinical Global Impressions-Severity (CGI-S) scale decreased in the omega-3/6 group, compared with a rapid decrease and subsequent slight increase in the MPH group. Also notable is that there were fewer adverse events in the omega-3/6 group and MPH + omega-3/6 group compared to the MPH alone group (Barragán et al 2017).

Clinical Application of Omega-3 in Psychiatric Diagnoses

The summary of clinical benefit appears as follows: It seems that efficacious dosage ranges of omega-3s vary in psychiatric disorders, and based on research, appear to be mainly at >2:1 ratios of EPA to DHA; BD and MDD 1-2g/d for a minimum of 12 weeks, ADHD – youth 500-750mg/d for a minimum of 16 weeks. The dosage of omega-3 used in schizophrenia seems to be approximately 2200mg/day for a minimum of 16 weeks.

As a general dosage overview, studies including a meta-analysis suggest that administration of at least 60% EPA, with total EPA dosage 200-2200mg greater than DHA dosage showed beneficial outcomes in depression (Sublette et al 2011). More specific findings, such as a recent study by Guu et al, suggested that MDD benefitted the most therapeutically from an administration of 1-2g of omega-3s as a ratio of >2:1 of EPA/DHA or just EPA alone (Guu et al 2019).

An additional study indicates clinical value in the following doses and durations for youth with ADHD and MDD. For ADHD, EPA and DHA ≥750 mg/d, as well as a larger dosage of EPA (1200mg/d) for those with inflammation/allergy for 16 to 24 weeks. For MDD, it was proposed that 1000-2000mg/d, designed in a 2:1 ratio of EPA:DHA for 12 to 16 weeks, was effective (Chang et al 2020).

A pivotal point worth delving further into is why EPA, more than DHA, was found to exhibit the anti-depressive effects. Kalkman et al (2021) have attempted to uncover the molecular/pharmacological pathways underlying this phenomenon that parallel the clinical effect. EPA is thought to have a greater role due to its use of the CYP monooxygenase pathway for EPA and EPA-derived eicosanoids, alongside the finding of greater affinity of CB2 and EPA/EPA metabolites versus DHA, and lastly, the incorporation of EPA into phosphatidylinositols, while DHA is mainly incorporated into phosphatidyl-ethanolamine/serine/choline (Kalkman et al 2021). These molecular differences could prove monumental for achieving therapeutic optimization and successful clinical outcomes.

Consideration For Therapeutic Optimization and Future Research

There are several concepts worth noting in the assessment of the use of omega-3s in psychiatric disease prior to personalizing and optimizing a treatment regimen, and for use in further research:

1. The baseline levels in individuals should be examined. Sometimes high levels of improvement are shown only in those with lower baseline levels of EPA/DHA to begin with.
2. The ratio of EPA/DHA is not always stated in the articles, which should be noted in the context of the result shift/outcome of success. A 2:1 ratio has been proposed to be more successful in psychiatric diagnoses than other ratios of EPA/DHA.
3. Consider if the patient has any other comorbidities. Is an equally measurable effect seen if omega-3s are used in individuals with heart disease and depression versus those with depression alone.
4. The practicality of clinical doses of omega-3s from the perspective of compliance in adults and children. Some studies have shown high clinical doses in ADHD that are not likely to encourage compliance in children, also the balance of effective dosing with gastrointestinal and skin-related side effects should be considered.
5. McDonnell et al (2019) showcased that the Omega-3 Index can correspond to an improvement in symptoms. At baseline individuals show significant variation in Omega-3 Index. Achieving an increase of Omega-3 Index of ≥8% resulted in improved health outcomes. While the trial focused on heart disease, it seems appropriate to consider a similar relationship and monitoring of the Omega-3 Index as a tool to guide intervention of N-3 PUFAs for management of mental health concerns.
6. Treatment response markers, such as inflammatory profiles and biomarkers, may determine how responsive an individual is to omega-3s and/or other treatments.
7. How the quality of the supplement might affect the molecular optimization and efficacy.

These questions will enable a more accurate application and understanding of omega-3 use in psychoses prior to designing a therapeutic protocol.

Conclusion

Overall, N-3 PUFAs are thought to be involved in the pathophysiology, treatment, and prevention of BD, ADHD, MDD, and schizophrenia. The clinical value from the studies mentioned above occurs at an average daily dose of 200-2200mg for psychiatric disorders for a duration of 12 to 24 weeks, based on the assessments of research in this article. The mechanisms of action involved are thought to include a low cellular/plasma EPA and DHA level, with the aim of supplementation to correct these lower levels. Further research and future directions of study are required to confirm this effect by designing studies with greater statistical power that could include a thorough examination of EPA: DHA ratios specific to each of these disorders. Nonetheless, many studies have already shown successful adjuvant treatment of omega-3s alongside conventional medicines with improvement at the cellular and clinical level. These findings warrant that omega-3s are a valuable and promising therapeutic candidate for psychiatric diagnoses.

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