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fatty acids in mood disorders\nFish-derived omega-3 fatty acids provide eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which help to maintain fluidity of the cell membrane, reduce inflammatory eicosanoids, and prevent the release of proinflammatory cytokines.57,116 Alpha linoleic acid also converts differentially into omega-3 fatty acids, EPA, and DHA. However, omega-6 fatty acids from domesticated animals and cultivated vegetables is consumed in much larger quantities than omega-3 fatty acids. Therefore, cell membranes acquire increasing proportions of omega-6 fatty acids that adversely affect membrane fluidity and flexibility.57,116 In contrast, supplementation of omega-3 fatty acids from fish oil in liquid or capsule form maintains cell membrane fluidity. Substitution of omega-6 fatty acids for omega-3 fatty acids in the cell membrane has been associated with unipolar and bipolar depression, which is thought to be due to loss of membrane fluidity and flexibility. The latter results in disturbance of membrane proteins, such as enzymes, receptors, ion channels, and neurotransmitters, which in turn increases levels of inflammatory eicosanoids and proinflammatory cytokines.57,116 In fact, a study of 12 women with bipolar disorder found that those treated with omega-3 fatty acid supplements showed significant improvement in membrane fluidity and flexibility.116 However, a review of the relevant literature on use of omega-3 fatty acids in depression yielded mixed results, although this could have been due to methodological differences between studies, the lower proportions of EPA and DHA used in those studies, and patient selection bias.117 In another review of 19 relevant studies, 13 reported a positive effect of omega-3 fatty acids in patients with depression, whereas six studies found no such association.118 In addition, a meta-analysis of relevant studies reported that \u003e60% EPA (out of the total of EPA and DHA, where dose range of 200–2200 mg/day of EPA in excess of DHA) had a positive impact on symptoms of depression compared with studies that used doses containing \u003c60% of total EPA and DHA.119 Finally, a placebo-controlled trial of adding omega-3 fatty acids to citalopram in patients with depression found significant improvement in depression scores compared with a placebo plus citalopram group, although there was no improvement in the speed of the initial antidepressant response.120\nAn increased risk of suicide, commonly associated with depression, has been linked with omega-3 fatty acid deficiency.121 A case-controlled study at autopsy compared omega-3 fatty acid levels in the orbitofrontal cortex of patients with major depressive disorder (n = 15) and age-matched controls (n = 27). Lower DHA levels were found in the orbitofrontal cortex of 32% of female patients and 16% in male patients,122 suggesting that lower levels of DHA could be a marker of increased suicide risk in patients with depression. Several other clinical trials support the adjunctive role of EPA and DHA in the treatment of both unipolar and bipolar depression.123–125 Omega-3 fatty acids are both safe during infant development and effective for the treatment of major depression in pregnant women. Notably, low fish consumption and omega-3 fatty acids have been linked with depression more in women than in men.126 Finally, a placebo-controlled study of 45 patients with bipolar disorder given omega-3 fatty acids ± cytidine found no significant effect on symptoms of depression compared with the placebo group.127 Cytidine, a pyrimidine, was reported to have antidepressant-like effects in preclinical studies. In summary, further research is needed before recommending use of omega-3 fatty acids as monotherapy in patients with major depressive and other mood disorders.\nOmega-3 fatty acids also have a preventive role. Interestingly, a lower lifetime prevalence of bipolar II disorder has been associated with greater consumption of seafood.128,129 Further, a small open-label study of bipolar I patients (n = 10) who were given EPA at a daily dose of 1.5–2.5 g found that eight of ten (80%) had a 50% decrease in depression scores.130 Subsequently, a randomized controlled trial has substantiated the adjunctive role of omega-3 fatty acids (6.2 g EPA plus 3.4 mg DHA and 1–2 g ethyl-EPA) in patients with bipolar II disorder receiving conventional mood stabilizers.131 A randomized controlled study of patients with bipolar disorder and rapid cycling who were receiving conventional treatment found that those given EPA 6 mg/day showed no significant difference in depressive or manic symptoms after four months of intervention than the group receiving placebo.132 These negative results might be due to the use of EPA without DHA and inclusion of patients with resistant rapid cycling. Thus, patients with dysphoria and rapid cycling should be given higher doses of EPA and DHA, probably 8–10 g/day.133 A recent meta-analysis of five pooled databases related to use of omega-3 fatty acids in bipolar patients found a significant reduction in symptoms of depression, although scores for mania were unaffected, thus supporting the adjunctive role of omega-3 fatty acids in the treatment of symptoms of depression in bipolar patients.134\nPregnant women often have depleted omega-3 fatty acid stores and are at higher risk for postpartum depression and bipolar depression.135 Almost all psychotropic medications carry a risk of side effects in pregnant women and may also adversely affect fetal and infant development. CAM therapies are safe alternatives in pregnant women with major depression. In randomized studies that used fixed doses136 or a range of doses (0.5, 1.4, 2.8 g/day) with no placebo controls,137 EPA and DHA (3–8 g/day) were found to be effective in pregnant women with major depression and postpartum depression, with no adverse effects on the fetus. However, researchers have suggested that these studies of omega-3 fatty acids need to be repeated in a larger sample of pregnant women with depression.136–137 S-adenosylmethionine, St John’s wort, bright light therapy, acupuncture, and exercise have also been reported to improve symptoms of depression in women.138 Further studies are needed to delineate specific CAM therapies useful in premenstrual syndrome, premenstrual dysphoric disorder, antepartum and postpartum depression, lactation, and transition through menopause.138–139\nOmega-3 fatty acids are also safe for use in children and adolescents with bipolar disorder. An 8-week open-label study of 20 children (aged 6–16 years) with bipolar disorder given EPA 1290 mg/day and DHA 4300 mg/day found that 35% of children had more than a 50% decrease in Young Mania rating scores,140 consistent with results in pediatric depression.141 Two-thirds of patients did not show improvement, indicating that omega-3 fatty acids are ineffective in pediatric bipolar disorder. However, larger studies are needed to confirm this. Pediatric bipolar disorder is a difficult condition to treat, and some pediatric bipolar patients may benefit from CAM therapies. One review has reported that omega-3 fatty acids and lecithin/choline have potential utility as CAM in pediatric bipolar disorder. S-adenosylmethionine and inositol have some data supporting their efficacy in the treatment of depressive symptoms. Some data suggest these compounds may be useful adjunctive treatments, but few data are available to support their use as stand-alone therapy in pediatric bipolar disorder.142 Another small open-label trial of a multinutrient supplement (EMPower™) found that 70% of pediatric completers with bipolar spectrum disorder demonstrated a significant decrease in both depression and mania scores between baseline and the final visit (P \u003c 0.05). Gastric discomfort was the only reported side effect. These researchers suggested that randomized, placebo-controlled trials of EMPower are warranted and feasible.143 Evidently, omega-3 fatty acid treatment was associated with a very modest improvement in symptoms of mania in children with bipolar disorder. The most commonly observed side effects of omega-3 fatty acids in children are nausea, heartburn, stomach pain, belching, bloating, and diarrhea attributable to higher doses and use of unrefined fish oil preparations. Bleeding episodes due to reduction in platelet aggregation and triggering of mania are other side effects of high doses of omega-3 fatty acids. Use of omega-3 fatty acids should be strictly avoided in patients on anticoagulant therapy and antidiabetic medications. Some omega-3 fatty acids found in fish oil can increase low-density lipoprotein cholesterol, which is bad for the heart.57"}

{"project":"2_test","denotations":[{"id":"23700366-15465995-76000670","span":{"begin":282,"end":285},"obj":"15465995"},{"id":"23700366-15465995-76000671","span":{"begin":659,"end":662},"obj":"15465995"},{"id":"23700366-15465995-76000672","span":{"begin":1214,"end":1217},"obj":"15465995"},{"id":"23700366-15465995-76000673","span":{"begin":1398,"end":1401},"obj":"15465995"},{"id":"23700366-16741195-76000674","span":{"begin":1682,"end":1685},"obj":"16741195"},{"id":"23700366-20586692-76000675","span":{"begin":1856,"end":1859},"obj":"20586692"},{"id":"23700366-21939614-76000676","span":{"begin":2150,"end":2153},"obj":"21939614"},{"id":"23700366-22198441-76000677","span":{"begin":2446,"end":2449},"obj":"22198441"},{"id":"23700366-16741213-76000678","span":{"begin":2568,"end":2571},"obj":"16741213"},{"id":"23700366-17188654-76000679","span":{"begin":2864,"end":2867},"obj":"17188654"},{"id":"23700366-17194275-76000680","span":{"begin":3107,"end":3110},"obj":"17194275"},{"id":"23700366-12888186-76000680","span":{"begin":3107,"end":3110},"obj":"12888186"},{"id":"23700366-11870016-76000680","span":{"begin":3107,"end":3110},"obj":"11870016"},{"id":"23700366-15555697-76000681","span":{"begin":3359,"end":3362},"obj":"15555697"},{"id":"23700366-22926607-76000682","span":{"begin":3559,"end":3562},"obj":"22926607"},{"id":"23700366-19515544-76000683","span":{"begin":3992,"end":3995},"obj":"19515544"},{"id":"23700366-14638594-76000684","span":{"begin":3996,"end":3999},"obj":"14638594"},{"id":"23700366-15960565-76000685","span":{"begin":4183,"end":4186},"obj":"15960565"},{"id":"23700366-16388069-76000686","span":{"begin":4417,"end":4420},"obj":"16388069"},{"id":"23700366-16814257-76000687","span":{"begin":4713,"end":4716},"obj":"16814257"},{"id":"23700366-19499625-76000688","span":{"begin":4952,"end":4955},"obj":"19499625"},{"id":"23700366-21903025-76000689","span":{"begin":5284,"end":5287},"obj":"21903025"},{"id":"23700366-12103448-76000690","span":{"begin":5421,"end":5424},"obj":"12103448"},{"id":"23700366-18370571-76000691","span":{"begin":5688,"end":5691},"obj":"18370571"},{"id":"23700366-16390366-76000692","span":{"begin":5759,"end":5762},"obj":"16390366"},{"id":"23700366-18370571-76000693","span":{"begin":6070,"end":6073},"obj":"18370571"},{"id":"23700366-16390366-76000693","span":{"begin":6070,"end":6073},"obj":"16390366"},{"id":"23700366-20385346-76000694","span":{"begin":6231,"end":6234},"obj":"20385346"},{"id":"23700366-20385346-76000695","span":{"begin":6446,"end":6449},"obj":"20385346"},{"id":"23700366-17258897-76000696","span":{"begin":6756,"end":6759},"obj":"17258897"},{"id":"23700366-18277369-76000697","span":{"begin":7545,"end":7548},"obj":"18277369"},{"id":"23700366-22747095-76000698","span":{"begin":7975,"end":7978},"obj":"22747095"}],"text":"Omega-3 fatty acids in mood disorders\nFish-derived omega-3 fatty acids provide eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which help to maintain fluidity of the cell membrane, reduce inflammatory eicosanoids, and prevent the release of proinflammatory cytokines.57,116 Alpha linoleic acid also converts differentially into omega-3 fatty acids, EPA, and DHA. However, omega-6 fatty acids from domesticated animals and cultivated vegetables is consumed in much larger quantities than omega-3 fatty acids. Therefore, cell membranes acquire increasing proportions of omega-6 fatty acids that adversely affect membrane fluidity and flexibility.57,116 In contrast, supplementation of omega-3 fatty acids from fish oil in liquid or capsule form maintains cell membrane fluidity. Substitution of omega-6 fatty acids for omega-3 fatty acids in the cell membrane has been associated with unipolar and bipolar depression, which is thought to be due to loss of membrane fluidity and flexibility. The latter results in disturbance of membrane proteins, such as enzymes, receptors, ion channels, and neurotransmitters, which in turn increases levels of inflammatory eicosanoids and proinflammatory cytokines.57,116 In fact, a study of 12 women with bipolar disorder found that those treated with omega-3 fatty acid supplements showed significant improvement in membrane fluidity and flexibility.116 However, a review of the relevant literature on use of omega-3 fatty acids in depression yielded mixed results, although this could have been due to methodological differences between studies, the lower proportions of EPA and DHA used in those studies, and patient selection bias.117 In another review of 19 relevant studies, 13 reported a positive effect of omega-3 fatty acids in patients with depression, whereas six studies found no such association.118 In addition, a meta-analysis of relevant studies reported that \u003e60% EPA (out of the total of EPA and DHA, where dose range of 200–2200 mg/day of EPA in excess of DHA) had a positive impact on symptoms of depression compared with studies that used doses containing \u003c60% of total EPA and DHA.119 Finally, a placebo-controlled trial of adding omega-3 fatty acids to citalopram in patients with depression found significant improvement in depression scores compared with a placebo plus citalopram group, although there was no improvement in the speed of the initial antidepressant response.120\nAn increased risk of suicide, commonly associated with depression, has been linked with omega-3 fatty acid deficiency.121 A case-controlled study at autopsy compared omega-3 fatty acid levels in the orbitofrontal cortex of patients with major depressive disorder (n = 15) and age-matched controls (n = 27). Lower DHA levels were found in the orbitofrontal cortex of 32% of female patients and 16% in male patients,122 suggesting that lower levels of DHA could be a marker of increased suicide risk in patients with depression. Several other clinical trials support the adjunctive role of EPA and DHA in the treatment of both unipolar and bipolar depression.123–125 Omega-3 fatty acids are both safe during infant development and effective for the treatment of major depression in pregnant women. Notably, low fish consumption and omega-3 fatty acids have been linked with depression more in women than in men.126 Finally, a placebo-controlled study of 45 patients with bipolar disorder given omega-3 fatty acids ± cytidine found no significant effect on symptoms of depression compared with the placebo group.127 Cytidine, a pyrimidine, was reported to have antidepressant-like effects in preclinical studies. In summary, further research is needed before recommending use of omega-3 fatty acids as monotherapy in patients with major depressive and other mood disorders.\nOmega-3 fatty acids also have a preventive role. Interestingly, a lower lifetime prevalence of bipolar II disorder has been associated with greater consumption of seafood.128,129 Further, a small open-label study of bipolar I patients (n = 10) who were given EPA at a daily dose of 1.5–2.5 g found that eight of ten (80%) had a 50% decrease in depression scores.130 Subsequently, a randomized controlled trial has substantiated the adjunctive role of omega-3 fatty acids (6.2 g EPA plus 3.4 mg DHA and 1–2 g ethyl-EPA) in patients with bipolar II disorder receiving conventional mood stabilizers.131 A randomized controlled study of patients with bipolar disorder and rapid cycling who were receiving conventional treatment found that those given EPA 6 mg/day showed no significant difference in depressive or manic symptoms after four months of intervention than the group receiving placebo.132 These negative results might be due to the use of EPA without DHA and inclusion of patients with resistant rapid cycling. Thus, patients with dysphoria and rapid cycling should be given higher doses of EPA and DHA, probably 8–10 g/day.133 A recent meta-analysis of five pooled databases related to use of omega-3 fatty acids in bipolar patients found a significant reduction in symptoms of depression, although scores for mania were unaffected, thus supporting the adjunctive role of omega-3 fatty acids in the treatment of symptoms of depression in bipolar patients.134\nPregnant women often have depleted omega-3 fatty acid stores and are at higher risk for postpartum depression and bipolar depression.135 Almost all psychotropic medications carry a risk of side effects in pregnant women and may also adversely affect fetal and infant development. CAM therapies are safe alternatives in pregnant women with major depression. In randomized studies that used fixed doses136 or a range of doses (0.5, 1.4, 2.8 g/day) with no placebo controls,137 EPA and DHA (3–8 g/day) were found to be effective in pregnant women with major depression and postpartum depression, with no adverse effects on the fetus. However, researchers have suggested that these studies of omega-3 fatty acids need to be repeated in a larger sample of pregnant women with depression.136–137 S-adenosylmethionine, St John’s wort, bright light therapy, acupuncture, and exercise have also been reported to improve symptoms of depression in women.138 Further studies are needed to delineate specific CAM therapies useful in premenstrual syndrome, premenstrual dysphoric disorder, antepartum and postpartum depression, lactation, and transition through menopause.138–139\nOmega-3 fatty acids are also safe for use in children and adolescents with bipolar disorder. An 8-week open-label study of 20 children (aged 6–16 years) with bipolar disorder given EPA 1290 mg/day and DHA 4300 mg/day found that 35% of children had more than a 50% decrease in Young Mania rating scores,140 consistent with results in pediatric depression.141 Two-thirds of patients did not show improvement, indicating that omega-3 fatty acids are ineffective in pediatric bipolar disorder. However, larger studies are needed to confirm this. Pediatric bipolar disorder is a difficult condition to treat, and some pediatric bipolar patients may benefit from CAM therapies. One review has reported that omega-3 fatty acids and lecithin/choline have potential utility as CAM in pediatric bipolar disorder. S-adenosylmethionine and inositol have some data supporting their efficacy in the treatment of depressive symptoms. Some data suggest these compounds may be useful adjunctive treatments, but few data are available to support their use as stand-alone therapy in pediatric bipolar disorder.142 Another small open-label trial of a multinutrient supplement (EMPower™) found that 70% of pediatric completers with bipolar spectrum disorder demonstrated a significant decrease in both depression and mania scores between baseline and the final visit (P \u003c 0.05). Gastric discomfort was the only reported side effect. These researchers suggested that randomized, placebo-controlled trials of EMPower are warranted and feasible.143 Evidently, omega-3 fatty acid treatment was associated with a very modest improvement in symptoms of mania in children with bipolar disorder. The most commonly observed side effects of omega-3 fatty acids in children are nausea, heartburn, stomach pain, belching, bloating, and diarrhea attributable to higher doses and use of unrefined fish oil preparations. Bleeding episodes due to reduction in platelet aggregation and triggering of mania are other side effects of high doses of omega-3 fatty acids. Use of omega-3 fatty acids should be strictly avoided in patients on anticoagulant therapy and antidiabetic medications. Some omega-3 fatty acids found in fish oil can increase low-density lipoprotein cholesterol, which is bad for the heart.57"}