By Rochelle Fernandes, MSc., ND (cand.)
Peer-reviewed by Makoto Trotter BSc(Hons), ND, Erin Wiley, ND, & Hilary Booth, ND, HBSc
Psychiatric diagnoses can be challenging to treat. While antipsychotic and antidepressant medications are designed to treat psychotic and affective symptoms, the effects are often suboptimal, and are accompanied by several side effects. There seems to be a growing need to supplement conventional treatment with naturopathic options in this group of disorders. As such, there has been an increasing interest and recent research on omega-3 supplementation in psychiatric disorders (schizophrenia, attention deficit hyperactivity disorder (ADHD), bipolar disorder and depression).
Mechanisms of action of omega-3 in psychiatric disorders
It has been hypothesized that 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, 2010), (Orr, 2013). Other activities include that n-3 PUFA increases membrane fluidity (Meijerink, 2013), activates peroxisome proliferator activated receptors, and enhances neurotrophic support (Kou, 2008). These multi-faceted mechanisms of action lend support for theories of possible neuroprotective and cognitive benefits in psychiatric disorders.
Reviews on the subject concluded that PUFAs and their mediators are responsible for certain processes within the central nervous system: (1) the maintenance of cell structure and function of neurons, glial cells and endothelial cells; (2) the regulation of neuro-inflammatory processes; and (3) the modulation of neurotransmission (Bazinet, 2014). These mechanisms provide a basis for mood regulation, symptom control and cognitive function. This enables an understanding of how n-3 PUFA may be a novel therapeutic target of interest in several psychiatric disorders, such as depression and schizophrenia.
It is thought that altered mechanisms of action, including, but not limited to 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, 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, 2003, McNamara, 2015). Cross-sectional studies have found that children with a very high risk for mood disorders have erythrocyte EPA and DHA deficits compared with healthy individuals (Clayton, 2008).
Well established erythrocyte EPA and DHA low levels were also seen in those with social anxiety disorder (Green, 2006), and plasma EPA and DHA deficits were found in those with major depression alongside comorbid anxiety disorders (Liu, 2013). 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, 2002). An interesting meta-analysis of 18 case-control studies also showed significant low levels of DHA and AA in schizophrenic individuals (Hoen, 2013). These studies suggest that deficits in erythrocyte DHA and AA may predispose patients to psychosis, and persist in those diagnosed.
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, 2014). The rationale behind the use of omega-3 supplementation is an intent to treat; correcting this deficiency.
Evidence for using omega-3 in schizophrenia
A growing body of evidence exists for the use of omega-3s in schizophrenia. When any dose of omega-3 ethyl-EPA (E-EPA or EPA) is compared with placebo, a small, short set of studies suggest that the need for neuroleptic medication seems to be decreased for people taking omega-3 (n=30, 1 RCT, RR 0.73 CI 0.54 to 1.00) and mental state may improve (n=30, 1 RCT, RR not gaining 25 per cent change in PANSS scores 0.54 CI 0.30 to 0.96, NNT3 CI 2-29) (Joy, 2006).
A Cochrane Review investigated the use of omega-3 and evening primrose oil to treat symptoms of schizophrenia. The review found a positive effect of EPA versus placebo for scale-derived mental state outcomes, in the context of symptom improvement. It should be noted that the data is preliminary and further studies with more power are necessary to confirm the effect to a greater degree. A smaller study within this review looked at using EPA as the only treatment for people hospitalized for relapse. The results showed that EPA may help 33 per cent of people who avoid using antipsychotic medication for twelve weeks (RR 0.6, CI 0.4-0.91) (Joy, 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, 2015).
One randomized, placebo controlled study provided clinical value by mention of dosage; 2,200 milligrams of n-3 PUFA or placebo was given for 26 weeks and the study evaluated symptoms in first episode schizophrenia. They concluded that this dosage was effective as an adjunctive therapy as per the following results: improvement of 50 per cent 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, 2016).
It should be noted that many studies used only EPA and/or did not always cite the ratio of EPA:DHA, however, this could be an interesting point for further examination. Overall, the dosage of omega-3 used in schizophrenia seems to be approximately 2,200 milligrams.
Evidence for using omega-3 in bipolar disorder, ADHD and depression
N3-PUFA is thought to be involved in the pathophysiology, treatment and prevention of bipolar disease (BD) (Sublette M. E., 2011). The protective function of n-3 PUFA was examined in patients with BD. DHA and EPA caused increased membrane fluidity, as detected by reductions in T2 (a membrane integrity marker) values, compared to controls in a four-week study (Hirashima, 2004).
A small, double-blind, placebo controlled trial 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 two grams of E-EPA per day or placebo 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 PUFA in BD that can be further examined with larger studies (Frango, 2007).
N-3 PUFA was also proposed to be useful in the treatment of ADHD. One meta-analysis showed that in the primary analyses, n-3 PUFA 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. This could indicate that larger sample sizes may amplify this effect and show value in highlighting the effects of n-3 PUFA on reducing EL in subsets of children with ADHD (Cooper, 2016). A randomized controlled trial showed that supplementation with n-3 PUFA 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, 2015).
Much like BD, n-3 PUFA has 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, 2016).
The clinical benefit appears as follows: it seems that dosage ranges of omega 3 vary in these disorders. However, several studies including a valuable meta-analysis suggested that an administration of at least 60 per cent or more of EPA, with a dosage range of 200 to 2,200 milligrams of EPA over the amount of DHA showed beneficial outcomes in depression (Sublette E. M., 2011).
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 is at an average dose of 200 to 2,200 milligrams for psychiatric disorders in this article. The mechanisms of action involved are thought to include a reduction or alteration of cellular/plasma EPA and DHA, with the aim of supplementation to correct this deficit. Further research and future directions of study are required to solidify 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 omega-3s as a valuable therapeutic option for psychiatric diagnoses.
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