Эйкозапентаеновая кислота как корректор интерферон-индуцированной депрессии

Background

Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression.

Methods

We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis.

Results

Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels.

Conclusions

EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.

Omega-3 Fatty Acids in the Prevention of Interferon-Alpha-Induced Depression: Results from a Randomized, Controlled Trial 

Метаболизм сфинголипидов и шизофрения

There is considerable evidence for specific pathology of lipid metabolism in schizophrenia, affecting polyunsaturated fatty acids and in particular sphingolipids. These deficits are assumed to interfere with neuronal membrane functioning and the development and maintenance of myelin sheaths. Recent studies suggest that some of these lipid pathologies might also be detected in peripheral skin tests. In this study, we examined different skin lipids and their relation to schizophrenia. We assessed epidermal lipid profiles in 22 first-episode antipsychotic-naïve schizophrenia patients and 22 healthy controls matched for age and gender using a hexan/ethanol extraction technique and combined high-performance thin-layer chromatography/gas-chromatography. We found highly significant increase of ceramide AH and NH/AS classes in patients and decrease of EOS and NP ceramide classes. This is the first demonstration of specific peripheral sphingolipid alterations in schizophrenia. The results support recent models of systemic lipid pathology and in particular of specific sphingolipids, which are crucial in neuronal membrane integrity. Given recent findings showing amelioration of psychopathology using fatty acid supplementation, our findings also bear relevance for sphingolipids as potential biomarkers of the disease.

 Skin Ceramide Alterations in First-Episode Schizophrenia Indicate Abnormal Sphingolipid Metabolism

Отсутствие эффективности диеты богатой омега-3 и омега-6 в предупреждении депрессии

Background: The associations between different sources of dietary n−3 (omega-3) and n−6 (omega-6) fatty acids and the risk of depression have not been prospectively studied.

Objective: The objective was to examine the relation between different n−3 and n−6 types with clinical depression incidence.

Design: We prospectively studied 54,632 US women from the Nurses' Health Study who were 50–77 y of age and free from depressive symptoms at baseline. Information on diet was obtained from validated food-frequency questionnaires. Clinical depression was defined as reporting both physician-diagnosed depression and regular antidepressant medication use.

Results: During 10 y of follow-up (1996–2006), 2823 incident cases of depression were documented. Intake of long-chain n−3 fatty acids from fish was not associated with depression risk [relative risk (RR) for 0.3 g/d increment: 0.99; 95% CI: 0.88, 1.10], whereas α-linolenic acid (ALA) intake was inversely associated with depression risk (multivariate RR for 0.5 g/d increment: 0.82; 95% CI: 0.71, 0.94]). The inverse association between ALA and depression was stronger in women with low linoleic acid (LA) intake (P for interaction = 0.02): a 0.5-g/d increment in ALA was inversely associated with depression in the first, second, and third LA quintiles [RR (95% CI): 0.57 (0.37, 0.87), 0.62 (0.41, 0.93), and 0.68 (0.47, 0.96), respectively] but not in the fourth and fifth quintiles.

Conclusions: The results of this large longitudinal study do not support a protective effect of long-chain n−3 from fish on depression risk. Although these data support the hypothesis that higher ALA and lower LA intakes reduce depression risk, this relation warrants further investigation.

Dietary intake of n−3 and n−6 fatty acids and the risk of clinical depression in women: a 10-y prospective follow-up study

Омега-3 ПНЖК в предупреждении развития психоза

Eighty-one putatively prodromal patients (16.4 years, 33.3% male) were included in this 12-month, randomized, double-blind, placebo-controlled trial comparing 1.2 g omega-3 PUFA (700 mg eicosapentaenoic acid [EPA] and 420 mg docosahexaenoic acid [DHEA]h) with placebo over 12 weeks with a follow-up of 40 weeks off medication/placebo. Randomization was stratified with regard to depressive symptoms (cut-off score on the Montgomery-Asberg Depression Rating Scale [MADRS]). Operationally defined conversion rates served as the outcome measure, with psychopathology ratings as secondary measures. Overall, this study had a very high 12-month completion rate (93.8%); adherence rates based on pill count and self-rating were as high as 81% and 75% in the active and placebo groups. The main result was that patients treated for 3 months with omega-3 PUFAs had significantly lower conversion rates to psychosis, at the end of the acute 3-month treatment phase and also after an additional 9 months off omega-3 PUFA (12-month conversion rate: 4.9% vs 27.5%). The number needed to treat (NNT) to prevent 1 additional patient with conversion to psychosis at 1 year was only 5. In addition, positive, negative, and general symptoms measured by the Positive and Negative Syndrome Scale (PANSS) were significantly more reduced in the active treatment group, whereas adverse events did not differ. Finally, the ratio of putatively beneficial omega-3 to omega-6 fatty acids increased significantly, linking the clinical effects to a proposed biological mechanism.

The Year in Psychosis and Bipolar Disorder: Omega-3s and Psychosis Prevention

антидепрессивный эффект эйкозапентаеновой кислоты

In fact, only eicosapentaenoic acid (EPA) — and not docosahexaenoic acid (DHA) — is associated with mood improvement in patients with depression, concluded lead study author John M. Davis, MD, research professor at the University of Illinois in Chicago.

The meta-analysis of 15 randomized, double-blind, placebo-controlled studies clarifies which type of omega-3 fatty acid is effective for depression and why previous findings on the antidepressant effects of omega-3 fatty acids have been contradictory, said Dr. Davis at a press conference.

Omega-3 fatty acids are not synthesized by the body and therefore must be consumed in food (primarily fish and nuts) or supplements. In food, EPA and DHA are found together in a 1:1 ratio, but supplements can contain either fatty acid or a combination of both, he said.

The study concluded that an EPA-predominant formulation is necessary for the full therapeutic antidepressant action, whereas the DHA-predominant formulation has little antidepressant efficacy.

Not All Omega-3s Equal When It Comes to Antidepressant Effects

Эффективность омеги-3 в предупреждении послеродовой депрессии

For this study, 2399 pregnant women at less than 21 weeks' gestation were enrolled between October 2005 and January 2008 at 1 of 5 Australian maternity hospitals. The women were then randomly assigned to receive either 800 mg daily of DHA-rich fish oil capsules (n = 1197) or matching vegetable oil capsules without DHA (placebo/control group, n = 1202) at baseline, continuing until they gave birth.

The mean age for both groups was 29.9 years, and the median gestational age at trial entry for both groups was 19.0 weeks.

Assessments for adverse gastrointestinal or bleeding events were conducted by telephone at 22, 28, and 36 weeks' gestation.

At 6 weeks and at 6 months postpartum, the mothers were assessed for depressive symptoms using the self-administered Edinburgh Postnatal Depression Scale. The study's primary maternal outcome was a high level of depressive symptoms, which was defined as "a score of more than 12."

Follow-ups were conducted with 694 of the children at the age of 18 months (DHA group, n = 333; placebo group, n = 361). The investigators used the Bayley Scales of Infant and Toddler Development, Third Edition, to evaluate both cognitive and language development.

Neurodevelopment was the study's primary childhood outcome. Secondary outcome measures included an evaluation scale of gross and fine motor functioning and parental report scales of social–emotional behavior and adaptive behavior.

Little to No Effect

Results showed that 96.7% of the enrolled women completed the study.

During the first 6 months postpartum, high levels of depressive symptoms in those taking the DHA capsules (9.67%) and those taking the placebo (11.19%) did not differ significantly (adjusted relative risk [RR], 0.85; 95% confidence interval [CI], 0.70 - 1.02; P = .09).

"Interestingly, our data did suggest a 3% to 4% reduction in depressive symptoms in the subgroup of women who had a previous history of depression," said Dr. Makrides. "It may be that these women [would] benefit from supplementation, but other studies are needed to confirm this."

However, "the percentage of women with a new medical diagnosis for depression during the trial or a diagnosis requiring treatment did not differ between groups," write the study authors.

There were also no significant differences in mean cognitive composite scores for the children of mothers in the DHA group vs those in the control group (adjusted mean difference, 0.01; 95% CI, −1.36 to 1.37; P = .99).

However, fewer infants in the DHA group had scores indicating delayed cognitive development than did those in the control group (2.71% vs 6.64%; P = .007).

Although there were no overall between-group differences in mean language composite scores (adjusted mean difference, −1.42; 95% CI, −3.07 to 0.22; P = .09), or between boys in both treatment groups, the girls in the DHA group had a lower mean language score (P < .001) and an increased risk for delayed language development (P = .03) than did the girls in the control group.

No overall between-group differences were found for motor development, social–emotional behavior, and adaptive behavior. However, the girls in the DHA group had poorer mean adaptive behavior scores than did those in the control group (P = .003).

The DHA-treated group had fewer preterm births of less than 34 weeks' gestation (1.09%) compared with those treated with placebo (2.25%; adjusted RR, 0.49; P = .03), but the DHA group had "more postterm births requiring obstetric intervention," including inductions or cesarean deliveries (17.59% vs 13.72%; adjusted RR, 1.28; P = .01).

"Clearly these trade-offs are important to consider, and it may be that DHA supplementation may be most useful to women at risk of having a preterm baby," noted Dr. Makrides.

Finally, at least 1 serious adverse event was reported for 36 of the DHA-group infants vs 54% of those in the control group (RR, 0.67; P = .06). Eructations were reported by more women in the DHA group than in the control group at both 28 weeks' (43.6% vs 25.6%) and 36 weeks' (41.5% vs 29.2%) gestation (P < .001 for both time points).

"This is the largest and most well-conducted study of its type, [and] we have a conclusive result about the fact that there is little or no effect of DHA supplementation during normal pregnancy on postpartum depression or early childhood neurodevelopment in the first 18 months of life," summarized Dr. Makrides.

No Benefit of DHA Fish Oil for Postpartum Depression, Child Neurodevelopment

Альтернативные методы лечения депрессий

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Although there is strong evidence that light therapy can counter seasonal depression, the efficacy of light therapy as a treatment for major depression is less well established. Also, it looks as if light therapy might be more effective against major depression if it is combined with an antidepressant than if used alone.

In one randomized, controlled trial, for instance, 102 subjects were treated with the SSRI sertraline (50 mg/d). Subjects also received randomized augmentation treatment with 30 minutes of either bright morning (10,000 lux) or dim red (50 lux) light for five weeks. All clinician and self-report measures significantly favored active light augmentation.
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Regarding St. John's wort, trials suggest that it is more effective for mild to moderate depression than for the severe form of the illness.
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Studies have failed to demonstrate the efficacy of acupuncture compared with a control condition for the treatment of major depression.
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And as for folate, its efficacy as a monotherapy for major depressive disorder has yet to be adequately tested. A few trials have found folate to be efficacious and well tolerated, although the best dose and form of folate remain unclear.

Alternative Treatments May Have Some Use in Depression

Новое в механизме действия лития

Though it has been prescribed for over 50 years to treat bipolar disorder, there are still many questions regarding exactly how lithium works. However, in a study appearing in this month's Journal of Lipid Research, researchers have provided solid evidence that lithium reduces brain inflammation by adjusting the metabolism of the health-protective omega-3-fatty acid called DHA.

Uncovering Lithium's Mode of Action

Омега-3, омега-6 и витамин D в предупреждении возникновения психотических симптомов

"Our findings raise a possibility that adult women with a high intake of fish, omega-3 or omega-6 PUFA and vitamin D have a lower rate of psychotic-like symptoms."

Dietary intake of fish, omega-3, omega-6 polyunsaturated fatty acids and vitamin D and the prevalence of psychotic-like symptoms in a cohort of 33 000 women from the general population

Использование омега-3 в терапии депрессии

The Essential Fatty Acids

There are 2 main types of essential fatty acids in humans, the ω-3 derived from a-linolenic acid and the v-6 series derived from linoleic acid. Although a-linolenic acid is easily converted to eicosapentaenoic acid (EPA), the conversion from a-linolenic acid to docosahexaenoic acid (DHA) is inefficient in humans (less than 0.1%).[3] Because essential fatty acids cannot be synthesized de novo, they must be obtained from the diet. a-Linolenic acid comes mainly from plant sources, such as flax and canola oil, while EPA and DHA are obtained from marine sources, such as tuna, salmon, mackerel, and sardines. On the other hand, the main sources of v-6 linoleic acid are seed oil–based margarines, soy oil, sunflower oil, and safflower oil. Linoleic acid alone accounts for 10% of all calories in the US diet and by suppressing conversion of a-linolenic acid, creates greater dietary requirements for EPA and DHA consumption to achieve adequate levels in tissue.[4]

Anthropological and epidemiological data indicate that humans evolved on a shore-based diet with abundant seafood and few calories from seed oils. This may have permitted hominid encephalization.[5] In contrast, typical Western diets are now nearly devoid of adequate seafood and have excessive linoleic acid. An excess of v-6 fatty acids leads to increased low-density lipoprotein oxidation, platelet aggregation, and alterations in the cell membrane structure. Thus, high dietary intakes of v-6 fatty acids may cause a shift toward the proinflammatory, prothrombotic, and proconstrictive state, thereby promoting the pathogenesis of many illnesses, such as cardiovascular disease and cancer.[6]

The Use of Omega-3 Fatty Acids in Treatment of Depression

Омега-3 в предупреждении ризвития психиатрических заболеваний

G. Paul Amminger, MD; Miriam R. Schäfer, MD; Konstantinos Papageorgiou, MD; Claudia M. Klier, MD; Sue M. Cotton, PhD; Susan M. Harrigan, MSc; Andrew Mackinnon, PhD; Patrick D. McGorry, MD, PhD; Gregor E. Berger, MD

Arch Gen Psychiatry. 2010;67(2):146-154.

Context The use of antipsychotic medication for the prevention of psychotic disorders is controversial. Long-chain {omega}-3 (omega-3) polyunsaturated fatty acids (PUFAs) may be beneficial in a range of psychiatric conditions, including schizophrenia. Given that {omega}-3 PUFAs are generally beneficial to health and without clinically relevant adverse effects, their preventive use in psychosis merits investigation.

Objective To determine whether {omega}-3 PUFAs reduce the rate of progression to first-episode psychotic disorder in adolescents and young adults aged 13 to 25 years with subthreshold psychosis.

Design Randomized, double-blind, placebo-controlled trial conducted between 2004 and 2007.

Setting Psychosis detection unit of a large public hospital in Vienna, Austria.

Participants Eighty-one individuals at ultra-high risk of psychotic disorder.

Interventions A 12-week intervention period of 1.2-g/d {omega}-3 PUFA or placebo was followed by a 40-week monitoring period; the total study period was 12 months.

Main Outcome Measures The primary outcome measure was transition to psychotic disorder. Secondary outcomes included symptomatic and functional changes. The ratio of {omega}-6 to {omega}-3 fatty acids in erythrocytes was used to index pretreatment vs posttreatment fatty acid composition.

Results Seventy-six of 81 participants (93.8%) completed the intervention. By study's end (12 months), 2 of 41 individuals (4.9%) in the {omega}-3 group and 11 of 40 (27.5%) in the placebo group had transitioned to psychotic disorder (P = .007). The difference between the groups in the cumulative risk of progression to full-threshold psychosis was 22.6% (95% confidence interval, 4.8-40.4). {omega}-3 Polyunsaturated fatty acids also significantly reduced positive symptoms (P = .01), negative symptoms (P = .02), and general symptoms (P = .01) and improved functioning (P = .002) compared with placebo. The incidence of adverse effects did not differ between the treatment groups.

Conclusions Long-chain {omega}-3 PUFAs reduce the risk of progression to psychotic disorder and may offer a safe and efficacious strategy for indicated prevention in young people with subthreshold psychotic states.

Long-Chain {omega}-3 Fatty Acids for Indicated Prevention of Psychotic Disorders

These individuals either had mild psychotic symptoms, transient psychosis or a family history of psychotic disorders plus a decrease in functioning. These criteria identify individuals whose risk of becoming psychotic may be as high as 40 percent in a 12-month period.

For 12 weeks, 41 individuals were assigned to take daily fish oil capsules containing 1.2 grams of omega-three polyunsaturated fatty acids and 40 were assigned to take placebo; a total of 76 (93.8 percent) completed the intervention. By the end of the study, two (4.9 percent) in the omega-3 group and 11 (27.5 percent) in the placebo group had transitioned to psychotic disorder. The difference between progression to psychosis was 22.6 percent.

Fish Oil May Reduce Risk of Schizophrenia

Средиземноморская диета снижает риск возникновения депрессии

Dr. Martinez-Gonzalez said the risk for depression was substantially lower in participants with higher adherence to the MDP and that depression rates were about 30% lower in those with the highest consumption of fruit, nuts, legumes, and monounsaturated vs saturated fats.

"The important thing regarding fish is that a very low consumption of fish (lowest quintile) was in fact a risk factor when it was compared with the 3 upper categories of fish consumption (merged together)," he added.

The researchers were trying to determine why the lifetime prevalence of mental disorders is lower in Mediterranean than Northern European countries. One possible factor is diet, as previous research has suggested that the monounsaturated fatty acids in olive oil — used abundantly in the Mediterranean diet — may be associated with a lower risk for severe depressive symptoms.

The study included 10,094 healthy Spanish participants who reported their dietary intake on a food frequency questionnaire. After a median follow-up of 4.4 years, there were 480 new cases of depression. Individuals who followed the Mediterranean diet most closely had a greater than 30% reduction in the risk for depression than whose who had the lowest Mediterranean diet scores. The association did not change when the results were adjusted for other markers of a healthy lifestyle.

The strength of the inverse association between the [MDP] and depression surprised the investigators. "The new question for us is that if these results will be reproduced in a primary prevention trial," Dr. Martinez-Gonzalez said. "Another new question is whether the MDP is longitudinally associated with increased serum levels of BDNF," or brain-derived neurotrophic factor — a peptide critical for axonal growth, neuronal survival, and synaptic plasticity.

According to the authors, "An emerging concept in neuroscience is that perturbations in the health of cerebral endothelium (such as some loss of the neuroprotection afforded by BDNF) may mediate progressive neuronal dysfunction." Depression is associated with low BDNF in some patients.

Mediterranean Diet Cut Depression Risk by 30%

Fatty Acid's Role in Alzheimer's Remains In Doubt

An omega-3 fatty acid (DHA) did not slow Alzheimer's, but it may help with prevention and sharpen the memories of seniors with normal age-related memory complaints.

The findings of this study "indicate that the use of 900 mg of . . . DHA per day improves learning and memory recall in healthy aging adults with mild memory complaints

Fatty Acid's Role in Alzheimer's Remains In Doubt

омега-3 эйкозапентаеновая кислота

Sixty outpatients with a diagnosis of major depressive disorder based on DSM-IV criteria and a score >or=15 in the 17-item Hamilton Depression Rating Scale (HDRS) were randomly allocated to receive daily either 1000 mg EPA or 20 mg fluoxetine, or their combination for 8 weeks...
In the present 8 week trial EPA and fluoxetine had equal therapeutic effects in major depressive disorder. EPA + fluoxetine combination was superior to either of them alone.
Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder