Role of Long-Chain Omega-3 Fatty Acids in Psychiatric Practice

Abstract

Nutrition plays a minor role in psychiatric practice which is currently dominated by a pharmacological treatment algorithm. An accumulating body of evidence has implicated deficits in the dietary essential long-chain omega-3 (LCn-3) fatty acids, eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology of several major psychiatric disorders. LCn-3 fatty acids have an established long-term safety record in the general population, and existing evidence suggests that increasing LCn-3 fatty acid status may reduce the risk for cardiovascular disease morbidity and mortality. LCn-3 fatty acid supplementation has been shown to augment the therapeutic efficacy of antidepressant, mood-stabilizer, and second generation antipsychotic medications, and may additionally mitigate adverse cardiometabolic side-effects. Preliminary evidence also suggests that LCn-3 fatty acid supplementation may be efficacious as monotherapy for primary and early secondary prevention and for perinatal symptoms. The overall cost-benefit ratio endorses the incorporation of LCn-3 fatty acids into psychiatric treatment algorithms. The recent availability of laboratory facilities that specialize in determining blood LCn-3 fatty acid status and emerging evidence-based consensus guidelines regarding safe and efficacious LCn-3 fatty acid dose ranges provide the infrastructure necessary for implementation. This article outlines the rationale for incorporating LCn-3 fatty acid treatment into psychiatric practice.

1. Introduction

Common psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, attention deficit hyperactivity disorder (ADHD), and anxiety disorders are chronic and typically recurring illnesses associated with significant psychosocial morbidity. Outcomes data indicate that mood and psychotic disorders are associated with excess premature mortality attributable primarily to suicide and cardiovascular-related diseases [1–4]. The initial onset of these disorders frequently occurs during adolescence or early adulthood [5–10], and psychiatric symptoms are typically initially treated with pharmacological agents including antidepressant, mood-stabilizer, and/or second generation antipsychotic medications. Symptomatic relapse following medication discontinuation is common [11–13], and patients typically require long-term prophylactic treatment per consensus guidelines. However, long-term treatment with some medications may be associated with adverse cardiometabolic side-effects [14] as well as other significant side effects [15,16] in a subset of vulnerable patients. These data highlight the need for safer and better tolerated treatments, or adjunctive treatments, to improve long-term outcomes for psychiatric patients.

While nutrition remains a largely neglected aspect of psychiatric treatment practice, a substantial body of evidence has emerged over the past two decades which has implicated a deficiency in dietary essential long-chain omega-3 (LCn-3) fatty acids, eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology of several major psychiatric disorders [17–20]. This is supported by evidence from cross-national and cross-sectional epidemiological surveys, case-control LCn-3 fatty acid composition studies, prospective observational and LCn-3 fatty acid intervention studies, and neurobiological studies in rodents. Additionally, accumulating evidence suggests that LCn-3 fatty acid deficiency may increase the risk of suicide and cardiovascular disease, two primary causes of excess premature mortality in patients with mood and psychotic disorders [1–4]. Based on the established long-term safety record of LCn-3 fatty acids in the general population, and multiple health benefits associated with increasing LCn-3 fatty acid status, the American Psychiatric Association has endorsed adjunctive treatment with LCn-3 fatty acids for the treatment of major depressive disorder [17]. However, the use of LCn-3 fatty acids in psychiatric practice remains limited and may be due to a lack of awareness of the evidence base supporting their beneficial role. This paper reviews evidence implicating LCn-3 fatty acid deficiency in the pathophysiology of psychiatric disorders and explores new roles for LCn-3 fatty acids in psychiatric treatment algorithms (Fig. 1).

Figure 1.

Proposed clinical staging model for LCn-3 fatty acid treatment of patients with or at high risk for developing schizophrenia or major depressive disorder. Stage I (primary prevention) proposes LCn-3 fatty acid monotherapy for subjects that are asymptomatic but are at high risk for developing a psychotic or mood disorder (i.e., they have a family history of psychiatric illness). For perinatal depression, LCn-3 fatty acid monotherapy may be proposed for treating symptoms when standard medications are contraindicated due to potential fetal teratogenic effects. Stage II (early secondary prevention) proposes LCn-3 fatty acid monotherapy for subjects exhibiting attenuated symptoms that do not meet criteria for a formal DSM-IV Axis I diagnosis (i.e., sub-syndromal). Stage III proposes adjunctive LCn-3 fatty acid treatment for patients with a formal DSM-IV diagnosis in conjunction with standard second generation antipsychotic (SGA) and/or selective serotonin reuptake inhibitor (SSRI) medications to augment efficacy and mitigate adverse cardiometabolic side effects. For treatment resistant depression, adjunctive LCn-3 fatty acid treatment in combination with SSRI and SGA medications may be considered.

2. LCn-3 fatty acid biosynthesis and status

As background, mammals require a dietary source of n-3 fatty acids to procure and maintain adequate LCn-3 fatty acid concentrations in peripheral and central tissues. Principal dietary sources of the vegetable short-chain n-3 fatty acid α-linolenic acid (ALA, 18:3n-3) include flaxseed, linseed, canola, soy, and perilla oils. The biosynthesis of LCn-3 fatty acids, including eicosapentaenoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3), from ALA requires a series of microsomal desaturation and elongation reactions, and the final synthesis of DHA requires β-oxidation within peroxisomes. In healthy adults residing in western countries, ALA→EPA biosynthesis is limited and ALA→DHA and EPA→DHA biosynthesis is negligible [21]. Accordingly, bypassing microsomal- and peroxisomal-mediated biosynthesis with preformed dietary LCn-3 fatty acids is significantly more effective than ALA for increasing EPA+DHA levels in peripheral and central tissues [22–25]. Principal dietary sources of preformed EPA+DHA include fatty cold water fish, including salmon, trout, tuna, as well as fish oil supplements [26].

An individual’s LCn-3 fatty acid ‘status’ can be determined by evaluating the fatty acid composition of blood (plasma phospholipids, erythrocytes, platelets), breast milk, and peripheral (e.g., adipose and cardiac biopsies) or central (i.e., postmortem brain) tissues by gas chromatography. Erythrocyte (red blood cell, RBC) membrane EPA+DHA composition has been found to provide a valid and relatively non-invasive index of habitual (1–2 months) dietary LCn-3 fatty acid intake [27–29]. Additionally, RBC EPA+DHA composition is positively correlated with blood plasma, platelet, immune cell [30,31], adipose [32,33], breast milk [34], myocardial [35], and brain gray matter [36, 37] EPA+DHA composition. Because RBC LCn-3 fatty acid levels may be influenced by other factors in addition to dietary intake, including age, genes, gender, and alcohol intake [38], predicting ones LCn-3 fatty acid status based on diet alone may not be accurate. Analogous to routine cholesterol testing, there has been a recent emergence of laboratory facilities that specialize in determining blood LCn-3 fatty acid levels, and there is emerging evidence-based consensus regarding optimal levels in the context of cardiovascular disease risk [39]. This infrastructure is anticipated to play an important role in other fields of medicine including psychiatry.

3. Psychiatric patients exhibit LCn-3 fatty acid deficiency

Several cross-sectional studies have investigated the LCn-3 fatty acid (EPA+DHA) ‘status’ of psychiatric patients. These studies have found that patients with MDD [40–45], bipolar disorder [45–47], schizophrenia [47–50], anxiety disorders [51] and ADHD [52–55] exhibit significant EPA+DHA deficits compared with demographically similar healthy subjects. A recent meta-analysis of 14 case-control fatty acid composition studies found that MDD patients exhibit significant RBC EPA+DHA deficits, whereas RBC levels of LCn-6 fatty acids including arachidonic acid (20:4n-6) do not differ between patients and healthy subjects [56]. The principle LCn-3 fatty acid found in brain gray matter is DHA, which comprises approximately 15% of total fatty acids composition [36], and RBC DHA composition is positively correlated with brain gray matter DHA composition [36,37]. Emerging evidence from human neuroimaging studies suggest that blood DHA levels are associated with different aspects of cortical structural and functional integrity relevant to psychiatric disorders [57]. Evidence also suggests that RBC EPA+DHA deficits precede or coincide with the initial onset of psychopathology [50,58]. Together, these findings suggest that RBC LCn-3 fatty acid deficiency may represent a general risk biomarker or risk factor associated with psychopathology.

While the etiology of LCn-3 fatty acid deficiency exhibited by psychiatric patients is likely multifactorial, understanding the underlying causes will have important implications for guiding treatment and prevention strategies. A number of findings suggest that deficiencies in oxidative defenses (i.e., alpha-tocopherol) are associated with increased susceptibility of RBC EPA+DHA to oxidative degradation [59–63]. It is also relevant that some studies have found that cigarette smoking, which is highly prevalent among patients with mood and psychotic disorders, is associated with elevated indices of RBC lipid peroxidation and lower EPA+DHA levels [64–66]. However, other findings suggest that elevated lipid peroxidation secondary to cigarette smoking cannot uniformly account for LCn-3 fatty acid deficits observed in psychiatric patients [38,46]. Additionally, heritable polymorphisms in the biosynthesis genes that mediate LCn-3 fatty acid biosynthesis may also be an important determinant of LCn-3 fatty acid status [67,68], and preliminary gene expression studies have observed alterations in the expression of biosynthesis genes in psychiatric patients [69–71]. Additionally or alternatively, evidence suggests that the LCn-3 fatty acid deficits observed in psychiatric patients are attributable to dietary LCn-3 fatty acid insufficiency [41,72]. Indeed, dietary LCn-3 fatty acid supplementation increases and normalizes RBC EPA+DHA composition in psychiatric patients [73,74]. Therefore, although the RBC EPA+DHA deficits observed in psychiatric patients may have a multifactorial etiology, they can be corrected with dietary LCn-3 fatty acid supplementation.

4. Rationale for treating LCn-3 fatty acid deficits in psychiatric patients

While beyond the scope of this review, there are several plausible biological mechanisms that could potentially mediate low LCn-3 fatty acid status observed in psychiatric patients and pathogenic mechanisms implicated in psychopathology. These mechanisms include a dysregulation in membrane signal transduction pathways [75], hypothalamic-pituitary-adrenal axis dysregulation [76–78], impaired neurotrophic production, neurogenesis and synaptogenesis during perinatal development [79–81], reduced neuronal resilience to physiological stressors [82], neurodevelopmental perturbations in serotonin [83–85] and dopamine [86–88] neurotransmission, and elevated pro-inflammatory immune signaling [89–91]. These and other examples provide a biological foundation linking LCn-3 fatty acid deficiency with relevant pathogenic processes, and additional clinical studies are warranted to evaluate whether these mechanisms can be modified by increasing LCn-3 fatty acid status.

More central to patient treatment, different lines of evidence suggest that LCn-3 fatty acid deficiency may represent a modifiable risk factor for psychiatric symptoms. First, cross-national epidemiological data indicate that greater habitual intake of fish and seafood (i.e., good dietary sources of LCn-3 fatty acids) are associated with reduced lifetime prevalence rates of unipolar depression and bipolar disorders [92–95]. Second, some cross-sectional studies [96–99], but not all [100,101], have observed an independent inverse association between low fish/seafood or fish oil intake and risk for developing depressive symptoms, particularly in women. Third, some prospective longitudinal observational studies [102–104] but not others [101,105] have observed an inverse association between baseline LCn-3 fatty acid intake/status and the subsequent emergence of depressive symptoms during the follow-up observation period. Fourth, retrospective studies suggest that population-wide shifts in habitual diets from fish-based to low LCn-3 ‘western diets’ are associated with increased rates of seasonal affective disorder, depression, and suicide [106]. Fifth, some fatty acid composition studies have observed an inverse correlation between plasma and/or RBC LCn-3 fatty acid composition, or LCn-3 fatty acid composition relative to LCn-6 composition (i.e., AA/EPA), and depression or manic symptom severity [72,107,108]. Sixth, prospective surveillance studies have found that low baseline LCn-3 fatty acid status is a predictor of depression development in human hepatitis C patients receiving interferon-α treatment [109,110] and the development of psychosis in ultra-high risk adolescents [111]. Although addition research is needed, this body of evidence suggests that low LCn-3 fatty acid status may represent a modifiable risk factor for mechanisms implicated in the progression of mood and psychotic disorders.

Consistent with this notion, independent meta-analyses of several small controlled LCn-3 fatty acid intervention trials have found a significant advantage of LCn-3 fatty acids over placebo in the treatment of syndromal depression [17,112,113]. Controlled and open-label trials have also found that LCn-3 supplementation, but not short-chain n-3 fatty acid supplementation [114], significantly reduces manic and/or depression symptom severity in pediatric and adolescent patients [73,74,115]. Importantly, reductions in manic and depression symptom severity following LCn-3 fatty acid supplementation were associated with increases in RBC EPA+DHA composition [73,74]. Accumulating evidence also suggests that LCn-3 fatty acid treatment may have benefits for positive and negative symptoms of schizophrenia, particularly when administered early in the course of illness [58,63,116–119]. A meta-analysis of controlled trials also found that LCn-3 fatty acid treatment produces a small but significant benefit for ADHD symptoms [120], and a preliminary controlled trial found that LCn-3 fatty acid treatment reduces anxiety symptoms in healthy subjects [121]. Although additional research is required to confirm and extend these findings, this body of evidence suggests that increasing LCn-3 fatty acid status has beneficial effects on different psychiatric symptoms.

Mood and psychotic disorders are associated with excess premature mortality primarily attributable to suicide [1–4], and several lines of evidence suggest that increasing LCn-3 fatty acid status may reduce suicide risk. First, cross-sectional epidemiological surveys have observed an inverse correlation between dietary LCn-3 fatty acid intake and the prevalence of suicidality [122], and that seasonal variations in suicide rates coincide with seasonal variations in serum LCn-3 fatty acid levels [123]. In two case-control studies, RBC or plasma LCn-3 fatty acid composition was found to be significantly reduced in suicidal patients [124,125], and a prospective surveillance study found that low baseline plasma DHA composition was a significant predictor of future suicidal attempts in medication-free patients with MDD [126]. Lastly, two controlled trials have found that chronic (12 week) dietary LCn-3 fatty acid treatment reduced suicidality in MDD patients [127,128]. While the mechanisms mediating this effect are not fully understood, these data suggest that increasing LCn-3 fatty acid status may have the added benefit of reducing suicide risk.

Excess premature mortality in psychiatric patients is also attributable to cardiovascular-related diseases [1–4], and multiple lines of evidence now suggest that LCn-3 fatty acid deficiency increases risk for cardiovascular disease morbidity and mortality [39]. Specifically, cross-national epidemiological surveys have observed reduced prevalence rates of cardiovascular disease in populations whose habitual diets include foods rich in LCn-3 fatty acids [129], and fatty acid composition studies have found an inverse correlation between RBC LCn-3 fatty acid status and cardiovascular risk factors [39]. Moreover, preclinical evidence suggests that LCn-3 fatty acids are protective against cardiac arrhythmias [130,131], and prospective studies have found that low baseline RBC LCn-3 fatty acid status is associated with increased risk of sudden cardiac arrest [132,133]. Intervention studies have found that increasing dietary LCn-3 fatty acid status reduces cardiovascular events and the incidence of sudden cardiac mortality [134–136]. It is relevant, therefore, that the low RBC EPA+DHA levels observed in patients with mood and psychotic disorders are similar to those observed in patients suffering acute coronary syndrome [137], and are associated with cardiovascular risk factors including elevated serum triglyceride and C-reactive protein (CRP) levels [138]. Together, these findings suggest that low LCn-3 fatty acid status may be an important determinant of premature excess mortality associated with cardiovascular disease in patients with psychiatric illnesses, and provides an independent rationale for LCn-3 fatty acid treatment.

4.1. Adjunctive LCn-3 fatty acid treatment

In the majority of prior controlled LCn-3 fatty acid intervention studies observing benefits for depressive symptoms [112,113], patients were also receiving conventional antidepressant medications. These data suggest that adjunctive LCn-3 fatty acid treatment augments the therapeutic efficacy of antidepressant medications. This is directly supported by two studies that compared selective serotonin reuptake inhibitor (SSRI) treatment with or without adjunctive LCn-3 fatty acids in patients with MDD. In both studies, adjunctive LCn-3 fatty acid treatment augmented the therapeutic efficacy of fluoxetine [139] or citalopram [140]. Additionally, adjunctive LCn-3 fatty acid treatment was found to reduce depression symptom severity in MDD patients that were refractory to standard antidepressant treatment [128]. Adjunctive LCn-3 fatty acid treatment was also found to reduce relapse rates in predominantly medicated adult patients with bipolar disorder [134], and to reduce manic symptom severity in medicated pediatric patients with bipolar disorder [74]. In first-episode psychotic patients, adjunctive LCn-3 fatty acid treatment was found to accelerate treatment response, improve tolerability, and permit a 20 percent reduction in second-generation antipsychotic (SGA) dose [135]. These preliminary findings suggest that adjunctive LCn-3 fatty acid treatment augments the therapeutic efficacy of conventional antidepressant, mood-stabilizer, and antipsychotic medications.

In addition to improving efficacy, adjunctive LCn-3 fatty acid treatment may also be protective against adverse cardiometabolic side effects associated with medication exposure. For example, SGA medications, including quetiapine, olanzapine, and risperidone, are associated with adverse cardiometabolic side-effects including elevated triglyceride levels and weight gain in the majority of first-episode patients [14]. This is a significant concern because these side-effects pose substantial long-term health risks in adulthood in an already vulnerable population [142–143]. Consistent with evidence that increasing LCn-3 fatty acid status is efficacious for lowering elevated triglyceride levels in the general population [144], studies have found that adjunctive LCn-3 fatty acid treatment significantly and dose-dependently decreased elevated fasting triglyceride levels in schizophrenic patients treated with clozapine [119,145]. Moreover, emerging evidence suggests that low LCn-3 fatty acid status is associated with increased waist circumference, overweight and obesity [146–149], and preliminary intervention studies have observed reductions in total fat mass, subcutaneous adipocyte diameter, and body mass index in adult overweight or obese patients following LCn-3 fatty acid supplementation [150–152]. Although prospective research is needed to confirm these protective effects, these preliminary findings suggests that adjunctive LCn-3 fatty acid treatment may mitigate adverse cardiometabolic side effects and weight gain following initiation of SGA treatment.

4.2. LCn-3 fatty acid monotherapy and clinical staging

The ‘clinical staging’ approach proposes that safer and better tolerated interventions be used for the treatment of symptoms in earlier stages of the illness, followed by more aggressive treatments that may pose greater health risks for non-responsive cases [153]. While this treatment model has been widely adopted by other fields of medicine including oncology, it is also heuristically valuable for guiding early interventions in children and adolescents with or at high risk for psychiatric disorders [154]. Although evidence from retrospective and prospective studies is beginning to elucidate prodromal criteria to identify individuals that are at ‘high risk’ for developing mood and psychotic disorders [154–156], prodromal symptoms may precede the onset of illness by many years necessitating that preventative interventions be safe and well tolerated with chronic exposure. Extant evidence further suggests that conventional medications may not be efficacious or well-tolerated for at risk youth [157]. Therefore, in view of the long-term safety and tolerability profile of LCn-3 fatty acids, they may be ideally suited for primary prevention in subjects meeting high risk criteria. As proof-of-concept, a double-blind trial randomized 81 patients at high risk for developing psychosis to 12-week treatment with 1.2 g/d of LCn-3 fatty acids or placebo, followed by a 40-week observation period after treatment cessation (12 months total) [58]. By the end of the 12-month treatment component, 2 of 41 individuals (4.9%) in the LCn-3 fatty acid arm and 11 of 40 (27.5%) in the placebo arm transitioned to threshold psychosis (p=0.007). It was concluded that LCn-3 fatty acids were efficacious for preventing or delaying psychosis transitioning in high risk patients. These preliminary data suggest that LCn-3 fatty acids may be efficacious and well-tolerated as a primary prevention intervention, and analogous trials are warranted in youth meeting high risk criteria for other psychiatric disorders.

In addition to primary prevention, LCn-3 fatty acid monotherapy may also have a role in early secondary prevention. Preliminary prospective intervention trials have found that LCn-3 fatty acid monotherapy significantly reduces symptom severity in pediatric and adolescent patients with MDD [115] or bipolar disorder [73]. For example, in a randomized, double-blind placebo-controlled trial conducted by Nemets et al., [115] children early in the course of depression received a placebo or LCn-3 fatty acid monotherapy for 16 weeks. The subjects treated with LCn-3 fatty acids exhibited significant reductions in depression symptom severity relative to subjects treated with placebo at week 8 which was sustained to week 16. Seventy percent of subjects treated with LCn-3 fatty acids, and none of the subjects treated with placebo, had a greater than 50% reduction in symptom severity, and 40% of subjects treated with LCn-3 fatty acids, and none of the subjects treated with placebo, exhibited symptomatic remission. In a separate study, LCn-3 fatty acid monotherapy was found to significantly reduce positive and negative symptom severity compared with placebo in patients at ultra-high risk for developing psychosis [58]. Although additional research is needed to confirm these preliminary findings, these data suggest that LCn-3 fatty acid monotherapy may be efficacious for the treatment of sub-syndromal as well as syndromal mood and psychotic symptoms in youth early in their illness course.

Additionally LCn-3 fatty acid monotherapy may also have a role in treating perinatal psychiatric symptoms when conventional medications may be contraindicated due to potential fetal teratogenic effects. For example, LCn-3 fatty acid monotherapy was found to reduce positive and negative symptom severity in a pregnant schizophrenic women following medication discontinuation [164]. Moreover, women experiencing postpartum depression exhibit plasma LCn-3 fatty acid deficits [158,159] and LCn-3 fatty acid treatment were found to reduce symptom severity in women with depression arising during pregnancy [160] or postpartum [161]. However, other studies did not observe preventative efficacy in women with [162] or without [163] a history of postpartum depression.

5. LCn-3 fatty acid safety and dosing considerations

Potential adverse events associated with LCn-3 fatty acid treatment include gastrointestinal disturbances, including nausea, diarrhea, gastroesophageal reflux, eructation, and less commonly emesis. In double-blind clinical trials of adult patients, the principal adverse events reported after chronic (8–12 weeks) treatment were gastrointestinal problems, and were considered mild and reported as frequently in patients receiving the olive oil placebo [17]. To minimize the gastrointestinal adverse events associated with LCn-3 fatty acids, patients should be instructed to take their pills with meals. Although taking fish oil at high doses (>3 g/d) has been associated in isolated cases with increased bleeding time in subjects also taking anticoagulant medications [165], controlled clinical trials have found that chronic high dose EPA+DHA alone or in combination with aspirin does not increase risk for clinically-significant increases in bleeding time [166–168]. Another safety consideration involves the potential threat of contamination of fish and seafood with methyl mercury, PCBs, and other environmental pollutants. However, most fish oil supplements are highly purified and do not exceed U.S. Food and Drug Administration (FDA) limits for methyl mercury and other environmental contaminants. As with all medications, patients should be informed of potential risks associated with LCn-3 fatty acids, and patients with an allergy to shellfish or seafood should be closely monitored.

The U.S. FDA considers doses up to 3 g/d of LCn-3 fatty acids to be ‘generally regarded as safe’, and the American Psychiatric Association has adopted the consensus recommendations of the American Heart Association for an EPA+DHA dose of 1 g/d [17]. The American Heart Association also recommends 3 g/d EPA+DHA for reducing elevated triglyceride levels. Prescription EPA+DHA (Lovaza^® in the US, Omacor^® in Europe, GlaxoSmithKline) and purified ethyl ester EPA containing no DHA (Vascepa™, Amarin Corporation) have been approved by the U.S. FDA for the treatment of hypertriglyceridemia (≥500 mg/dL) at a dose of 4 g/d. A free versus ethyl ester EPA+DHA formulation (Epanova, Omthera Pharmaceuticals Inc.) found to result in greater free fatty acid bioavailability is currently in development [169], and a vegetarian (i.e., algal-derived) EPA+DHA supplement option is also available. It is important to note, however, that LCn-3 fatty acids are not currently approved by the FDA for the treatment of any psychiatric disorder. Nevertheless, over-the-counter fish oil supplements containing similar capsule ethyl ester EPA+DHA concentrations are widely available to consumers at substantially lower costs.

Controlled intervention studies have found that doses in the range of 1–4 g/d of EPA+DHA in a 2:1 EPA to DHA ratio are efficacious for the treatment of mood symptoms [17,113]. Emerging evidence also suggests that a larger ratio of EPA to DHA may be more efficacious for treating depressive symptoms [170] as well as ADHD symptoms [120]. Furthermore, 1–4 g/d of EPA+DHA significantly increases RBC EPA+DHA composition to levels similar to those observed in healthy subjects in Japan [171], where the life-time prevalence rates of mood disorders are among the lowest in the world [95]. As with other medications, upward dose titration may be required as clinically indicated. In an open-label flexible dosing study, 8-week LCn-3 fatty acid monotherapy led to a statistically significant reduction in manic symptom severity scores in pediatric bipolar patients [73]. In this study the starting dose was 1.3 g/d of EPA+DHA, the maximum dose was 4.3 g/d, and the mean dose was 2.6 g/d. In this and other studies conducted in pediatric patients, no clinically-significant treatment-emergent adverse events were reported following long-term (8–16 weeks) EPA+DHA treatment at doses up to 4.3 g/d [74,115]. While there is a clear need for additional dose-ranging and dose-titrating secondary prevention trials to elucidate optimal LCn-3 fatty acid dosing strategies, existing evidence suggests that EPA+DHA doses in the range of 1–4 g/d are safe and well-tolerated in pediatric, adolescent, and adult psychiatric patients.

6. Clinical Vignette

Patient A., a 20 year old undergraduate student who met DSM-IV-TR criteria for major depressive disorder, recurrent, without psychotic features or generalized anxiety disorder, presented for treatment following a psychiatric hospitalization which was precipitated by increasing suicidal ideation. During his inpatient hospitalization, citalopram monotherapy was initiated at a dose of 20 mg daily and was continued following his discharge. Despite excellent compliance, A. continued to experience significant depressive symptoms, including depressed mood, guilt, anhedonia, weight gain, hyperphagia and hypersomnia. Following treatment with citalopram at a dose of 20 mg daily for approximately 4 weeks, citalopram was increased to 40 mg daily. However, A’s depressive symptoms were only mildly reduced and he continued to experience significant functional impairment. Augmentation with low-dose quetiapine (12.5 mg to 25 mg QHS) was attempted, though this was not tolerated secondary to excessive sedation and accentuation of weight gain and was discontinued. At that time, citalopram was increased to 60 mg daily. However, A. continued to report persistent depressed mood and a heavy neurovegetative burden, including anergia, hypersomnia and hyperphagia. Treatment with adjunctive LCn-3 fatty acids was initiated at a dose of 2.4 g daily (EPA: 1.6 g, DHA: 0.8 g, 4 capsules per day, OmegaRx^®). Over the next 10 weeks, A’s score on the Children Depression Rating Scale-Revised (CDRS-R) decreased from 30 to 21 and he noted less depressed mood and moderate improvement in his neurovegetative symptoms. Moreover, his initially low red blood cell EPA+DHA composition (2.8% of total fatty acids) increased ~2-fold to 5.5% of total fatty acids following 10 week LCn-3 fatty acid treatment. He has continued to take adjunctive LCn-3 fatty acids for 12 months in addition to citalopram 60 mg daily. Importantly, A. has returned to school, is doing well academically and socially and his major depressive disorder has remained in remission. This case illustrates both the benefit and tolerability of adjunctive LCn-3 fatty acid treatment for patients exhibiting partial response to conventional antidepressant medications.

7. Summary and conclusions

There is now a substantial body of evidence that LCn-3 fatty acid deficiency is associated with pathophysiological mechanisms implicated in the progression of different psychiatric disorders, and may contribute risk to principle causes of excess premature mortality including suicide and cardiovascular disease. Emerging evidence suggests that LCn-3 fatty acids augment the therapeutic efficacy of antidepressant, mood-stabilizer, and SGA medications, and may additionally mitigate the adverse cardiometabolic side-effects associated with SGA medications. Preliminary evidence also suggests that LCn-3 fatty acids have efficacy as a primary prevention for high risk youth, for early secondary prevention within a ‘clinical staging’ framework, and for treating psychiatric symptoms during and following pregnancy. Additionally, LCn-3 fatty acids have an established long-term safety record and the overall cost-benefit ratio provides a strong rationale for incorporating LCn-3 fatty acid treatment into psychiatric treatment algorithms. The recent emergence of laboratory facilities that specialize in determining blood LCn-3 fatty acid status, emerging evidence-based consensus regarding optimal dosing regimens, and the availability of prescription and over-the-counter LCn-3 fatty acid supplements provide the infrastructure required for implementation.

Layperson's summary.

Nutrition plays a minor role in psychiatric practice which is currently dominated by a pharmacological treatment algorithm. An accumulating body of evidence has implicated deficits in the dietary essential long-chain omega-3 (LCn-3) fatty acids in the pathophysiology and treatment of several major psychiatric disorders. The overall cost-benefit ratio endorses the incorporation of LCn-3 fatty acids into psychiatric treatment algorithms.