Erectile Dysfunction, Omega-3, and Lipoic Acid

Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial.

AIMS: To investigate the prevalence of erectile dysfunction (ED) in patients with CAD according to clinical presentation, acute coronary syndrome (ACS) vs. chronic coronary syndrome (CCS), and extent of vessel involvement (single vs. multi-vessel disease). METHODS AND RESULTS: 285 patients with CAD divided into three age-matched groups: group 1 (G1, n=95), ACS and one-vessel disease (1-VD); group 2 (G2, n=95), ACS and 2,3-VD; group 3 (G3, n=95), chronic CS. Control group (C, n=95) was composed of patients with suspected CAD who were found to have entirely normal coronary arteries by angiography. Gensini’s score used to assess extent of CAD. ED as any value <26 according to the International Index of Erectile Function (IIEF). ED prevalence was lower in G1 vs. G3 (22 vs. 65%, P<.0001) as a result of less atherosclerotic burden as expressed by Gensini’s score [2 (0-6) vs. 40 (19-68), P=0.0001]. Controls had ED rate values similar to G1 (24%). Group 2 ED rate, IIEF, and Gensini’s scores were significantly different from G1 [55%, P<0.0001; 24 (17-29), P=0.0001; 21 (12.5-32), P<0.0001] and similar to G3 suggesting that despite similar clinical presentation, ED in ACS differs according to the extent of CAD. No significant difference between groups was found in the number and type of conventional risk factors. Treatment with beta-blockers was more frequent in G3 vs. G1 and G2. In G3 patients who had ED, onset of sexual dysfunction occurred before CAD onset in 93%, with a mean time interval of 24 [12-36] months. In logistic regression analysis, age (OR=1.1; 95% confidence interval (CI), 1.05-1.16; P=<0.0001), multi-vessel vs. single-vessel (OR=2.53; 95% CI, 1.43-4.51; P=0.0002), and CCS vs. ACS (OR=2.32; 95% CI, 1.22-4.41; P=0.01) were independent predictors of ED. CONCLUSION: ED prevalence differs across subsets of patients with CAD and is related to coronary clinical presentation and extent of CAD. In patients with established CAD, ED comes before CAD in the majority by an average of 2 up to 3 years.

Eur Heart J. 2006 Nov;27(22):2632-9

Is the metabolic syndrome an independent risk factor for erectile dysfunction?

PURPOSE: We determined the role of the metabolic syndrome as an independent risk factor for erectile dysfunction. MATERIALS AND METHODS: Men participating in a health screening project completed the International Index of Erectile Function-5. The metabolic syndrome was defined according to the 2005 International Diabetes Federation consensus definition. Multiple linear regression, ANOVA and chi-square tests were used to investigate the impact of the metabolic syndrome on erectile dysfunction. RESULTS: A total of 2,371 men with a mean age of 46.1 years (SD 9.9, range 30 to 69) were analyzed. Of the men 33.4% (652) had no erectile dysfunction (International Index of Erectile Function-5 score 22 to 25), 59.7% (1,166) had mild erectile dysfunction (International Index of Erectile Function-5 score 17 to 21) and 6.9% (134) had moderate to severe erectile dysfunction (International Index of Erectile Function-5 score 5 to 16). The metabolic syndrome was present in 33.8% (794). In a multiple linear regression analysis an increased waist-to-hip ratio (p = 0.01) and metabolic syndrome (p = 0.01) turned out to be independently associated with a decreased International Index of Erectile Function-5 score. When stratified according to age, the metabolic syndrome was correlated to erectile dysfunction only in men 50 years old or older with an increase of severe erectile dysfunction by 48% (p = 0.01). CONCLUSIONS: The metabolic syndrome and an increased waist-to-hip ratio are independently associated with a decreased International Index of Erectile Function-5 score. The metabolic syndrome in men older than 50 years is significantly associated with a higher proportion of moderate to severe erectile dysfunction.

J Urol. 2007 Feb;177(2):651-4

Does testosterone have a role in erectile function?

PURPOSE: Despite the well-established role of testosterone in enhancing libido, its exact contribution to erections in men remains unclear. The main objectives of this review are to clarify the role of testosterone in erectile function and evaluate its therapeutic value in men with erectile dysfunction (ED). METHODS: Review of the relevant literature (English, French, and Spanish) from 1939 to June 2005 was conducted using data sources from MEDLINE, endocrinology text books, and hand searching of cross-references from original articles and reviews. Clinical trials, animal studies, case reports, reviews, and guidelines of major associations were included. RESULTS: Animal and preliminary human studies suggest that testosterone may facilitate erection by acting as vasodilator of the penile arterioles and cavernous sinusoids. Following castration, most, but not all, men had partial or complete loss of erection. Hypogonadism is not a common finding in ED, occurring in about 5% of cases, and in general, there is lack of association between serum testosterone levels, when present in normal or moderately low levels, and erectile function. Most trials using testosterone for treatment of ED in hypogonadal men suffer from methodological problems and report inconsistent results, but overall, suggest that testosterone may be superior to placebo. Erectile function is more likely to improve with testosterone therapy in patients with severe degrees of hypogonadism. Testosterone treatment may ameliorate the response to the phosphodiesterase 5 (PDE5) inhibitors in hypogonadal men and men with low-normal serum testosterone. Repeated measurement of morning serum total testosterone is a fairly accurate and easy method to evaluate androgenecity, but measurement of free or bioavailable testosterone is recommended in conditions that alter the levels of sex-hormone-binding globulin (SHBG), such as in the elderly and in obesity. CONCLUSIONS: Available data suggest that in most men circulating levels of testosterone, well below the normal range, are essential for normal erection and that higher levels of serum testosterone may not have major impact on erectile function. Screening for hypogonadism in all men with ED is necessary to identify cases of severe hypogonadism and some cases of mild to moderate hypogonadism, who may benefit from testosterone treatment.

Am J Med. 2006 May;119(5):373-82

Dehydroepiandrosterone in the treatment of erectile dysfunction: a prospective, double-blind, randomized, placebo-controlled study.

OBJECTIVES: In 1994, the Massachusetts Male Aging Study presented an inverse correlation of the serum levels of dehydroepiandrosterone (DHEA) and the incidence of erectile dysfunction (ED). We evaluated the efficacy of DHEA replacement in the treatment of ED in a prospective, double-blind, randomized, placebo-controlled study. METHODS: The inclusion criteria included ED, normal physical and neurologic examinations, serum levels of testosterone, dihydrotestosterone, prolactin, and prostate-specific antigen (PSA) within the normal range, and a serum DHEA sulfate level below 1.5 micromol/L. Also all patients had a full erection after a pharmacologic erection test with 100 microg prostaglandin E1; pharmacocavernosography showed no visualization in corporeal venous structures. Forty patients from our impotence clinic were recruited and randomly divided into two groups of 20 patients each. Group 1 was treated with an oral dose of 50 mg DHEA and group 2 with a placebo one time a day for 6 months. The International Index of Erectile Function (IIEF), a 15-item questionnaire, was used to rate the success of this therapy. RESULTS: Therapy response was defined as the ability to achieve or maintain an erection sufficient for satisfactory sexual performance according to the National Institutes of Health Consensus Development Panel on Impotence. DHEA treatment was associated with higher mean scores for all five domains of the IIEF. There was no impact of DHEA treatment on the mean serum levels of PSA, prolactin, testosterone, the mean prostate volume, and the mean postvoid residual urine volume. CONCLUSIONS: Our results suggest that oral DHEA treatment may be of benefit in the treatment of ED. Although our patient data base is too small to do relevant statistical analysis, we believe that our data show a biologically obvious trend that justifies further extended studies.

Urology. 1999 Mar;53(3):590-4; discussion 594-5

Ginkgo biloba for antidepressant-induced sexual dysfunction.

In an open trial ginkgo biloba, an extract derived from the leaf of the Chinese ginkgo tree and noted for its cerebral enhancing effects, was found to be 84% effective in treating antidepressant-induced sexual dysfunction predominately caused by selective serotonin reuptake inhibitors (SSRIs, N = 63). Women (n = 33) were more responsive to the sexually enhancing effects of ginkgo biloba than men (N = 30), with relative success rates of 91% versus 76%. Ginkgo biloba generally had a positive effect on all 4 phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm, and resolution (afterglow). This study originated from the observation that a geriatric patient on ginkgo biloba for memory enhancement noted improved erections. Patients exhibited sexual dysfunction secondary to a variety of antidepressant medications including selective serotonin reuptake inhibitor (SSRIs), serotonin and nonrepinephrine reuptake inhibitor (SNRIs) monoamine oxidase inhibitor (MAOIs), and tricyclics. Dosages of ginkgo biloba extract ranged from 60 mg qd to 120 mg bid (average = 209mg/d). The common side effects were gastrointestinal disturbances, headache, and general central nervous system activation. The article includes a discussion of presumed pharmacologic mechanisms, including effects on platelet activating factor, prostaglandins, peripheral vasodilatation, and central serotonin and norepinephrine receptor factor modulation.

J Sex Marital Ther. 1998 Apr-Jun;24(2):139-43

Clinical efficacy of Korean red ginseng for erectile dysfunction.

To investigate the efficacy in treating erectile dysfunction and to develop a natural drug without complications, the results of ginseng treatments are compared to placebo and other drug. A total of 90 patients with 30 patients in each group were closely followed. Changes in symptoms such as frequency of intercourse, premature ejaculation, and morning erections after treatment were not changed in all three groups (p > 0.05). However in the group receiving ginseng, changes in early detumescence and erectile parameters such as penile rigidity and girth, libido and patient satisfactions were significantly higher than that of other groups (p < 0.05). The overall therapeutic efficacies on erectile dysfunction were 60% for ginseng group and 30% for placebo and trazodone treated groups, statistically confirming the effect of ginseng (p < 0.05). No complete remission of erectile dysfunction was noted, but partial responses were reported. No cases of aggravation of symptoms were reported. AVS-penogram, which is a recording of penile hemodynamic changes during the natural erection after audiovisual erotic stimulation, is not changed after administration of ginseng. However if administered for a prolonged period of time, the cummulative effect on vascular flow might be seen. The administration of Korean red ginseng has shown to have superior effects compared to the placebo or trazodone. Definitely more researches are required to elucidate the mechanism of ginseng. The effects of saponin, extracted from ginseng, on smooth muscle of erectile tissues, can be evaluated using organ chamber or nitric oxide titration, thereby pinpointing the exact action mechanism of saponin. As more informations are available, possible breakthrough in treatment of erectile dysfunction could be arisen from active saponin extracted from red ginseng, bringing hopes to many sufferers of erectile dysfunction.

Int J Impot Res. 1995 Sep;7(3):181-6

A double-blind crossover study evaluating the efficacy of Korean red ginseng in patients with erectile dysfunction: a preliminary report.

PURPOSE: We investigated the efficacy of Korean red ginseng for erectile dysfunction using the International Index of Erectile Function, RigiScan (UroHealth Systems, Laguna Niguel, California), hormonal levels and penile duplex ultrasonography with audiovisual sexual stimulation. MATERIALS AND METHODS: A total of 45 patients with clinically diagnosed erectile dysfunction were enrolled in a double-blind, placebo controlled, crossover study (8 weeks on treatment, 2 weeks of washout and 8 weeks on treatment) in which the effects of Korean red ginseng and a vehicle placebo were compared using multiple variables. The ginseng dose was 900 mg, 3 times daily. RESULTS: Mean International Index of Erectile Function scores were significantly higher in patients treated with Korean red ginseng than in those who received placebo (baseline 28.0 +/- 16.7 and 38.1 +/- 16.6 versus 30.9 +/- 15.7, p <0.01). Scores on questions 3 (penetration) and 4 (maintenance) were significantly higher in the ginseng than in the placebo group (p <0.01). In response to the global efficacy question 60% of the patients answered that Korean red ginseng improved erection (p <0.01). Among other variables penile tip rigidity on RigiScan showed significant improvement for ginseng versus placebo. CONCLUSIONS: Our data show that Korean red ginseng can be as effective alternative for treating male erectile dysfunction.

J Urol. 2002 Nov;168(5):2070-3

Sexual function in men older than 50 years of age: results from the health professionals follow-up study.

BACKGROUND: Although many studies have provided data on erectile dysfunction in specific settings, few studies have been large enough to precisely examine age-specific prevalence and correlates. OBJECTIVE: To describe the association between age and several aspects of sexual functioning in men older than 50 years of age. DESIGN: Cross-sectional analysis of data from a prospective cohort study. SETTING: US health professionals. PARTICIPANTS: 31,742 men, age 53 to 90 years. MEASUREMENTS: Questionnaires mailed in 2000 asked about sexual function, physical activity, body weight, smoking, marital status, medical conditions, and medications. Previous biennial questionnaires since 1986 asked about date of birth, alcohol intake, and other health information. RESULTS: When men with prostate cancer were excluded, the age-standardized prevalence of erectile dysfunction in the previous 3 months was 33%. Many aspects of sexual function (including overall function, desire, orgasm, and overall ability) decreased sharply by decade after 50 years of age. Physical activity was associated with lower risk for erectile dysfunction (multivariable relative risk, 0.7 [95% CI, 0.6 to 0.7] for >32.6 metabolic equivalent hours of exercise per week vs. 0 to 2.7 metabolic equivalent hours of exercise per week), and obesity was associated with higher risk (relative risk, 1.3 [CI, 1.2 to 1.4] for body mass index >28.7 kg/m2 vs. <23.2 kg/m2). Smoking, alcohol consumption, and television viewing time were also associated with increased prevalence of erectile dysfunction. Men who had no chronic medical conditions and engaged in healthy behaviors had the lowest prevalence. CONCLUSIONS: Several modifiable health behaviors were associated with maintenance of good erectile function, even after comorbid conditions were considered. Lifestyle factors most strongly associated with erectile dysfunction were physical activity and leanness.

Ann Intern Med. 2003 Aug 5;139(3):161-8

Fish oil and mental health: the role of n-3 long-chain polyunsaturated fatty acids in cognitive development and neurological disorders.

Epidemiological and experimental studies have indicated that consumption of more n-3 long-chain polyunsaturated fatty acids may reduce the risk for a variety of diseases, including cardiovascular, neurological and immunological disorders, diabetes and cancer. This article focuses on the role of marine n-3 long-chain polyunsaturated fatty acids in brain functions, including the development of the central nervous system and neurological disorders. An overview of the major animal studies and clinical trials is provided here, focusing on fatty acid supplementation during pregnancy and infancy, and prevention and management of Alzheimer’s disease, schizophrenia, depression and attention deficit hyperactive disorder. Although an optimal balance in n-3/n-6 long-chain polyunsaturated fatty acid ratio is important for proper neurodevelopment and cognitive functions, results from randomized controlled trials are controversial and do not confirm any useful effect of supplementation on development of preterm and term infants. The relationship between fatty acid status and mental disorders is confirmed by reduced levels of n-3 long-chain polyunsaturated fatty acids in erythrocyte membranes of patients with central nervous system disorders. Nevertheless, there are very little data supporting the use of fish oil in those patients. The only way to verify whether n-3 long-chain polyunsaturated fatty acids are a potential therapeutic option in the management and prevention of mental disorders is to conduct a large definitive randomized controlled trials similar to those required for the licensing of any new pharmacological treatment.

Int Clin Psychopharmacol. 2006 Nov;21(6):319-36

Associations between cod liver oil use and symptoms of depression: the Hordaland Health Study.

BACKGROUND: Clinical trials suggest that omega-3 fatty acids improve the outcome of depression. This study aimed to evaluate the association between intake of cod liver oil, rich in omega-3 fatty acids, and high levels of symptoms of depression and anxiety in the general population. METHODS: We used data from the “The Hordaland Health Study ‘97-’99” (HUSK), a population based cross-sectional health survey from Norway including 21,835 subjects aged 40-49 and 70-74 years. Symptoms of depression and anxiety were measured by The Hospital Anxiety and Depression Scale (HADS). We used logistic regression to study associations. RESULTS: Among the participants, 8.9% used cod liver oil daily. A total of 3.6% had high levels of depressive symptoms. The prevalence of such depressive symptoms among the subjects who used cod liver oil daily was 2.5%, as compared to 3.8% in the rest of the population. The users of cod liver oil were significantly less likely to have depressive symptoms than non-users after adjusting for multiple possible confounding factors (odds ratio=0.71, 95% confidence interval 0.52 to 0.97). These factors included age, gender, smoking habits, coffee consumption, alcohol consumption, physical activity, and education. In addition, we found that the prevalence of high levels of depressive symptoms decreased with increasing duration (0-12 months) of cod liver oil use (multivariate adjusted test for trend, P=0.04). We were only able to study this latter association in a subset of the population aged 40-46 years. LIMITATIONS: Data are cross sectional. CONCLUSIONS: The findings indicate that regular use of cod liver oil is negatively associated with high levels of depressive symptoms in the general population.

J Affect Disord. 2007 Aug;101(1-3):245-9

Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial.

BACKGROUND: Trials have demonstrated benefits of long-chain omega-3 essential fatty acid (n-3 EFA) supplementation in a variety of psychiatric disorders. AIMS: To assess the efficacy of n-3 EFAs in improving psychological well-being in patients with recurrent self-harm. METHOD: Patients (n=49) presenting after an act of repeated self-harm were randomised to receive 1.2 g eicosapentaenoic acid plus 0.9 g decosahexaenoic acid (n=22) or placebo (n=27) for 12 weeks in addition to standard psychiatric care. Six psychological domains were measured at baseline and end point. RESULTS: At 12 weeks, the n-3 EFA group had significantly greater improvements in scores for depression, suicidality and daily stresses. Scores for impulsivity, aggression and hostility did not differ. CONCLUSIONS: Supplementation achieved substantial reductions in surrogate markers of suicidal behaviour and improvements in well-being. Larger studies are warranted to determine if insufficient dietary intake of n-3 EFAs is a reversible risk factor for self-harm.

Br J Psychiatry. 2007 Feb;190:118-22

Relationship between omega-3 fatty acids and plasma neuroactive steroids in alcoholism, depression and controls.

Deficiency in the long-chain omega-3 fatty acid, docosahexaenoic acid (DHA) has been associated with increased corticotropin releasing hormone and may contribute to hypothalamic pituitary axis (HPA) hyperactivity. Elevated levels of the neuroactive steroids, allopregnanolone (3alpha,5alpha-THP) and 3alpha,5alpha-tetrahydrodeoxycorticosterone (THDOC) appear to counter-regulate HPA hyperactivity. Plasma essential fatty acids and neurosteroids were assessed among 18 male healthy controls and among 34 male psychiatric patients with DSM-III alcoholism, depression, or both. Among all subjects, lower plasma DHA was correlated with higher plasma THDOC (r = -0.3, P < 0.05) and dihydroprogesterone (DHP) (r = -0.52, P < 0.05). Among psychiatric patients lower DHA was correlated with higher DHP (r = -0.60, P < 0.01), and among healthy controls lower plasma DHA was correlated with higher THDOC (r = -0.83, P < 0.01) and higher isopregnanolone (3beta,5alpha-THP) (r = -0.55, P < 0.05). In this pilot observational study, lower long-chain omega-3 essential fatty acid status was associated with higher neuroactive steroid concentrations, possibly indicating increased feedback inhibition of the HPA axis.

Prostaglandins Leukot Essent Fatty Acids. 2006 Oct-Nov;75(4-5):309-14

Omega-3 fatty acid deficiency in major depressive disorder is caused by the interaction between diet and a genetically determined abnormality in phospholipid metabolism.

Omega-3 fatty acids are a type of polyunsaturated fatty acid (PUFA). A growing body of evidence suggests that this form PUFA is a useful and well tolerated treatment for major depressive disorder, a common and serious mental illness. The efficacy of omega-3 PUFA is routinely explained as being due to a deficiency caused by inadequate dietary intake of this class of fatty acid. The hypothesis considered states that low omega-3 PUFA abundance in patients with major depressive and related disorders is due to an underlying genetically determined abnormality. The hypothesis can explain why although a specific and consistent deficit in omega-3, but not omega-6, PUFA occurs in major depressive and related disorders, the literature does not consistently support the notion that this is due to deficient dietary intake. Specifically it is hypothesized that having genetically determined low activity of fatty acid CoA ligase 4 and/or Type IV phospholipase A(2) combined with the low dietary availability of omega-3 PUFA results in reduced cellular uptake of omega-3 PUFA and constitutes a risk factor for depression. The hypothesis also has important consequences for the pharmacological treatment of depression in that it predicts that administering agents which enhance phospholipid synthesis, particularly those containing ethanolamine such as CDP-ethanolamine, should be effective antidepressants especially when co-administered with omega-3 PUFA.

Med Hypotheses. 2007;68(3):515-24. Epub 2006 Oct 12

Serum omega-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers.

Low dietary intake of omega-3 polyunsaturated fatty acids has been linked to several features of psychiatric symptomatology, including depression, disorders of impulse control, and hostility. Preliminary intervention trials of omega-3 fatty acid supplementation for clinical depression and other disorders have reported benefit. However, few studies have investigated the relationships between these fatty acids and normative variability in mood, behavior and personality. Participants were 105 hypercholesterolemic, but otherwise healthy, non-smoking adults. Fasting serum alpha-linolenic (alpha-LNA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) were assayed with gas chromatography. Participants completed the Beck Depression Inventory (BDI), the NEO Five Factor Personality Inventory (NEO-FFI) and the Barratt Impulsiveness Scale (BIS). In multivariate analyses, higher levels of the long chain omega-3 PUFAs, EPA and DHA, were associated with significantly reduced odds of scoring >/=10 on the BDI. Similarly, DHA and EPA covaried inversely with NEO-Neuroticism scores, whereas DHA was positively associated with NEO-Agreeableness. On the BIS, DHA was inversely related to cognitive impulsivity and alpha-LNA was inversely related to motor and total impulsivity. These findings suggest that omega-3 fatty acid status is associated with variability in affect regulation, personality and impulse control.

Psychiatry Res. 2007 Jul 30;152(1):1-10. Epub 2007 Mar 23

Long-chain omega-3 fatty acid intake is associated positively with corticolimbic gray matter volume in healthy adults.

BACKGROUND: In animals, dendritic arborization and levels of brain derived neurotrophic factor are positively associated with intake of the omega-3 fatty acids. Here, we test whether omega-3 fatty acid intake in humans varies with individual differences in gray matter volume, an in vivo, systems-level index of neuronal integrity. METHODS: Fifty-five healthy adults completed two 24h dietary recall interviews. Intake of long-chain omega-3 fatty acids was categorized by tertiles. Regional gray matter volumes in a putative emotional brain circuitry comprised of the anterior cingulate cortex (ACC), amygdala and hippocampus were calculated using optimized voxel-based morphometry on high-resolution structural magnetic resonance images. RESULTS: Region of interest analyses revealed positive associations between reported dietary omega-3 intake and gray matter volume in the subgenual ACC, the right hippocampus and the right amygdala, adjusted for total gray matter volume of brain. Unconstrained whole-brain analyses confirmed that higher intake of omega-3 fatty acids was selectively associated with increased greater gray matter volume in these and not other regions. CONCLUSIONS: Higher reported consumption of the long-chain omega-3 fatty acids is associated with greater gray matter volume in nodes of a corticolimbic circuitry supporting emotional arousal and regulation. Such associations may mediate previously observed effects of omega-3 fatty acids on memory, mood and affect regulation.

Neurosci Lett. 2007 Jun 29;421(3):209-12

Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder.

BACKGROUND:Epidemiological surveys and peripheral tissue (red blood cells/plasma) fatty acid composition studies suggest that omega-3 fatty acid deficiency is associated with major depressive disorder (MDD) and suicide. It was hypothesized that patients with MDD would exhibit lower frontal cortical concentrations of docosahexaenoic acid (DHA), the principal omega-3 fatty acid in brain, relative to normal controls. METHODS: We determined the total fatty acid composition of postmortem orbitofrontal cortex (Brodmann’s Area 10) from patients with DSM-IV-defined MDD (n = 15) and age-matched normal controls (n = 27) by gas chromatography. RESULTS: After correction for multiple comparisons, the omega-3 fatty acid DHA was the only fatty acid that was significantly different (-22%) in the postmortem orbitofrontal cortex of MDD patients relative to normal controls. Deficits in DHA concentrations were greater in female MDD patients (-32%) than in male MDD patients (-16%), and could not be wholly attributed to lifestyle factors or postmortem tissue variables. CONCLUSIONS: These results demonstrate a selective deficit in the omega-3 fatty acid DHA in the orbitofrontal cortex of patients with MDD. This finding adds to a growing body of evidence implicating omega-3 fatty acid deficiency as well as the orbitofrontal cortex in the pathophysiology and potentially pathogenesis of MDD.

Biol Psychiatry. 2007 Jul 1;62(1):17-24

Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study.

BACKGROUND: Indications have been seen of a protective effect of fish consumption and the intake of n-3 fatty acids on cognitive decline. However, studies are scarce and results inconsistent. OBJECTIVE: The objective of the study was to examine the associations between fish consumption, the intake of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish and other foods, and subsequent 5-y cognitive decline. DESIGN: Data on fish consumption of 210 participants in the Zutphen Elderly Study, who were aged 70-89 y in 1990, and data on cognitive functioning collected in 1990 and 1995 were used in the study. The intake of EPA and DHA (EPA+DHA) was calculated for each participant. Multivariate linear regression analysis with multiple adjustments was used to assess associations. RESULTS: Fish consumers had significantly (P = 0.01) less 5-y subsequent cognitive decline than did nonconsumers. A linear trend was observed for the relation between the intake of EPA+DHA and cognitive decline (P = 0.01). An average difference of approximately 380 mg/d in EPA+DHA intake was associated with a 1.1-point difference in cognitive decline (P = 0.01). CONCLUSIONS: A moderate intake of EPA+DHA may postpone cognitive decline in elderly men. Results from other studies are needed before definite conclusions about this association can be drawn.

Am J Clin Nutr. 2007 Apr;85(4):1142-7

Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study.

BACKGROUND: Seafood is the predominant source of omega-3 fatty acids, which are essential for optimum neural development. However, in the USA, women are advised to limit their seafood intake during pregnancy to 340 g per week. We used the Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the possible benefits and hazards to a child’s development of different levels of maternal seafood intake during pregnancy. METHODS: 11,875 pregnant women completed a food frequency questionnaire assessing seafood consumption at 32 weeks’ gestation. Multivariable logistic regression models including 28 potential confounders assessing social disadvantage, perinatal, and dietary items were used to compare developmental, behavioural, and cognitive outcomes of the children from age 6 months to 8 years in women consuming none, some (1-340 g per week), and >340 g per week. FINDINGS: After adjustment, maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ) (no seafood consumption, odds ratio [OR] 1.48, 95% CI 1.16-1.90; some, 1.09, 0.92-1.29; overall trend, p=0.004), compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor, communication, and social development scores. For each outcome measure, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome. INTERPRETATION: Maternal seafood consumption of less than 340 g per week in pregnancy did not protect children from adverse outcomes; rather, we recorded beneficial effects on child development with maternal seafood intakes of more than 340 g per week, suggesting that advice to limit seafood consumption could actually be detrimental. These results show that risks from the loss of nutrients were greater than the risks of harm from exposure to trace contaminants in 340 g seafood eaten weekly.

Lancet. 2007 Feb 17;369(9561):578-85

Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease.

Mitochondria produce reactive oxygen species that may contribute to vascular dysfunction. alpha-Lipoic acid and acetyl-L-carnitine reduce oxidative stress and improve mitochondrial function. In a double-blind crossover study, the authors examined the effects of combined alpha-lipoic acid/acetyl-L-carnitine treatment and placebo (8 weeks per treatment) on vasodilator function and blood pressure in 36 subjects with coronary artery disease. Active treatment increased brachial artery diameter by 2.3% (P=.008), consistent with reduced arterial tone. Active treatment tended to decrease systolic blood pressure for the whole group (P=.07) and had a significant effect in the subgroup with blood pressure above the median (151+/-20 to 142+/-18 mm Hg; P=.03) and in the subgroup with the metabolic syndrome (139+/-21 to 130+/-18 mm Hg; P=.03). Thus, mitochondrial dysfunction may contribute to the regulation of blood pressure and vascular tone. Further studies are needed to confirm these findings and determine the clinical utility of alpha-lipoic acid/acetyl-L-carnitine as antihypertensive therapy.

J Clin Hypertens (Greenwich). 2007 Apr;9(4):249-55

Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial.

OBJECTIVE: The aim of this trial was to evaluate the effects of alpha-lipoic acid (ALA) on positive sensory symptoms and neuropathic deficits in diabetic patients with distal symmetric polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 181 diabetic patients in Russia and Israel received once-daily oral doses of 600 mg (n = 45) (ALA600), 1,200 mg (n = 47) (ALA1200), and 1,800 mg (ALA1800) of ALA (n = 46) or placebo (n = 43) for 5 weeks after a 1-week placebo run-in period. The primary outcome measure was the change from baseline of the Total Symptom Score (TSS), including stabbing pain, burning pain, paresthesia, and asleep numbness of the feet. Secondary end points included individual symptoms of TSS, Neuropathy Symptoms and Change (NSC) score, Neuropathy Impairment Score (NIS), and patients’ global assessment of efficacy. RESULTS: Mean TSS did not differ significantly at baseline among the treatment groups and on average decreased by 4.9 points (51%) in ALA600, 4.5 (48%) in ALA1200, and 4.7 (52%) in ALA1800 compared with 2.9 points (32%) in the placebo group (all P < 0.05 vs. placebo). The corresponding response rates (>/=50% reduction in TSS) were 62, 50, 56, and 26%, respectively. Significant improvements favoring all three ALA groups were also noted for stabbing and burning pain, the NSC score, and the patients’ global assessment of efficacy. The NIS was numerically reduced. Safety analysis showed a dose-dependent increase in nausea, vomiting, and vertigo. CONCLUSIONS: Oral treatment with ALA for 5 weeks improved neuropathic symptoms and deficits in patients with DSP. An oral dose of 600 mg once daily appears to provide the optimum risk-to-benefit ratio.

Diabetes Care. 2006 Nov;29(11):2365-70

Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that destroys patient memory and cognition, communication ability with the social environment and the ability to carry out daily activities. Despite extensive research into the pathogenesis of AD, a neuroprotective treatment —particularly for the early stages of disease—remains unavailable for clinical use. In this review, we advance the suggestion that lipoic acid (LA) may fulfil this therapeutic need. A naturally occurring precursor of an essential cofactor for mitochondrial enzymes, including pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH), LA has been shown to have a variety of properties which can interfere with pathogenic principles of AD. For example, LA increases acetylcholine (ACh) production by activation of choline acetyltransferase and increases glucose uptake, thus supplying more acetyl-CoA for the production of ACh. LA chelates redox-active transition metals, thus inhibiting the formation of hydroxyl radicals and also scavenges reactive oxygen species (ROS), thereby increasing the levels of reduced glutathione. Via the same mechanisms, downregulation redox-sensitive inflammatory processes is also achieved. Furthermore, LA can scavenge lipid peroxidation products such as hydroxynonenal and acrolein. The reduced form of LA, dihydrolipoic acid (DHLA), is the active compound responsible for most of these beneficial effects. R-alpha-LA can be applied instead of DHLA, as it is reduced by mitochondrial lipoamide dehydrogenase, a part of the PDH complex. In this review, the properties of LA are explored with particular emphasis on how this agent, particularly the R-alpha-enantiomer, may be effective to treat AD and related dementias.

Pharmacol Ther. 2007 Jan;113(1):154-64

A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis.

BACKGROUND: Impaired mitochondrial phosphorylation potential may play a role in migraine pathogenesis. Metabolic enhancers, such as riboflavin or coenzyme Q, are effective in migraine prophylaxis and quasi-devoid of adverse effects. Thioctic acid (-lipoic acid) is another substance known to enhance energy metabolism in mitochondria and to be beneficial in diabetic neuropathy. OBJECTIVE: After an open pilot study suggesting its therapeutic antimigraine potentials, we embarked therefore in a randomized controlled trial of thioctic acid (Thioctacid) in migraine prophylaxis steered by the Belgian Headache Society. METHODS: Five Belgian centers recruited 54 migraineurs (43 migraine without aura, 11 with aura; mean age 38 +/- 8 years; 7 males). After a 1-month single-blinded run-in period, 44 patients received either placebo (n = 18) or thioctic acid 600 mg p.o./day (n = 26) for 3 months. RESULTS: Statistical analysis was carried out on an intention-to-treat basis. Monthly attack frequency tended to be reduced between run-in and the 3rd month of treatment in the thioctic acid group compared to placebo (P= .06). The proportion of 50% responders was not significantly different between thioctic acid (30.8%) and placebo (27.8%). Within-group analyses showed a significant reduction of attack frequency (P= .005), headache days (P= .009), and headache severity (P= .03) in patients treated with thioctic acid for 3 months, while these outcome measures remained unchanged in the placebo group. No adverse effects were reported. For logistical reasons this trial was interrupted before the planned 80 patients were enrolled. CONCLUSION: Albeit underpowered, this study tends to indicate that thioctic acid may be beneficial in migraine prophylaxis. Before any firm conclusion can be drawn, however, a large multicenter trial is necessary.

Headache. 2007 Jan;47(1):52-7

Randomized, placebo-controlled, double blind study on the clinical efficacy of a cream containing 5% alpha-lipoic acid related to photoageing of facial skin.

BACKGROUND: alpha-lipoic acid (LA) or the reduced form dihydrolipoate (DHLA) is a potent scavenger with anti-inflammatory properties. Previous uncontrolled studies with topical treatment with 5% LA-containing creams indicate a beneficial effect on photoageing skin. OBJECTIVE: The purpose of this study was to investigate whether a cream containing 5% LA showed any advantages concerning a number of the criteria associated with ageing of the facial skin, compared with an identical cream lacking LA. MATERIAL AND METHODS: Thirty-three women, mean age 54.4 years, were included in this controlled study. After randomization half the face was treated twice daily for 12 weeks with the LA cream and the other half with the control cream. The following methods of assessment were used: self-evaluation by the test subjects, clinical evaluation, photographic evaluation and laser profilometry. Profilometry was performed before the start of treatment and at the end. RESULTS: All four methods of assessment showed a statistically significant improvement on the LA-treated half of the face. Laser profilometry, the most objective method used, showed an average decrease in skin roughness of 50.8% (44.9-54.0) on the LA-treated side, compared with 40.7% (32.4-48.7) on the placebo-treated half of the face P < 0.001 (Wilcoxon matched pairs test). CONCLUSIONS: It is indicated that 12 weeks of treatment with a cream containing 5% LA improves clinical characteristics related to photoageing of facial skin.

Br J Dermatol. 2003 Oct;149(4):841-9

Alpha lipoic acid inhibits human T-cell migration: implications for multiple sclerosis.

We have demonstrated previously the ability of the antioxidant alpha lipoic acid (ALA) to suppress and treat a model of multiple sclerosis (MS), relapsing experimental autoimmune encephalomyelitis (EAE). We describe the effects of ALA and its reduced form, dihydrolipoic acid (DHLA), on the transmigration of human Jurkat T cells across a fibronectin barrier in a transwell system. ALA and DHLA inhibited migration of Jurkat cells in a dose-dependent fashion by 16-75%. ALA and DHLA reduced matrix metalloproteinase-9 (MMP-9) activity by 18-90% in Jurkat cell supernatants. GM6001, a synthetic inhibitor of MMP, reduced Jurkat cell migration, but not as effectively as ALA and DHLA did. Both ALA and DHLA downmodulated the surface expression of the alpha4beta1 integrin (very late activation-4 antigen; VLA-4), which binds fibronectin and its endothelial cell ligand vascular cell adhesion molecule-1 (VCAM-1). Moreover, ALA, but not DHLA, reduced MMP-9-specific mRNA and extracellular MMP-9 from Jurkat cells and their culture supernatants as detected by relative reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. ALA and DHLA inhibited Jurkat cell migration and have different mechanisms for inhibiting MMP-9 activity. These data, coupled with its ability to treat relapsing EAE, suggest that ALA warrants investigation as a therapy for MS.

J Neurosci Res. 2004 Nov 1;78(3):362-70

Antioxidants reduce cone cell death in a model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a label for a group of diseases caused by a large number of mutations that result in rod photoreceptor cell death followed by gradual death of cones. The mechanism of cone cell death is uncertain. Rods are a major source of oxygen utilization in the retina and, after rods die, the level of oxygen in the outer retina is increased. In this study, we used the rd1 mouse model of RP to test the hypothesis that cones die from oxidative damage. A mixture of antioxidants was selected to try to maximize protection against oxidative damage achievable by exogenous supplements; alpha-tocopherol (200 mg/kg), ascorbic acid (250 mg/kg), Mn(III)tetrakis (4-benzoic acid) porphyrin (10 mg/kg), and alpha-lipoic acid (100 mg/kg). Mice were treated with daily injections of the mixture or each component alone between postnatal day (P)18 and P35. Between P18 and P35, there was an increase in two biomarkers of oxidative damage, carbonyl adducts measured by ELISA and immunohistochemical staining for acrolein, in the retinas of rd1 mice. The staining for acrolein in remaining cones at P35 was eliminated in antioxidant-treated rd1 mice, confirming that the treatment markedly reduced oxidative damage in cones; this was accompanied by a 2-fold increase in cone cell density and a 50% increase in medium-wavelength cone opsin mRNA. Antioxidants also caused some preservation of cone function based upon photopic electroretinograms. These data support the hypothesis that gradual cone cell death after rod cell death in RP is due to oxidative damage, and that antioxidant therapy may provide benefit.

Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11300-5

Neuroprotection by the metabolic antioxidant alpha-lipoic acid.

Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders.

Free Radic Biol Med. 1997;22(1-2):359-78

Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2+ toxicity in isolated hepatocytes.

Lipoate (thioctic acid) is presently used in therapy of a variety of diseases such as liver and neurological disorders. However, nothing is known about the efficacy of lipoate and its reduced form dihydrolipoate in acute cadmium (Cd2+) toxicity which involves severe liver disturbances. Therefore, we investigated the effects of these redox compounds on Cd2(+)-induced injuries in isolated rat hepatocytes. The cells were coincubated with 150 microM Cd2+ and either 1.5-6.0 mM lipoate or 17-89 microM dihydrolipoate for up to 90 min and Cd2+ uptake as well as viability criteria were monitored. Both exposure regimens diminished Cd2+ uptake in correspondence to time and concentration. They also ameliorated Cd2(+)-induced cell deterioration as reflected by the decrease in Cd2(+)-induced membrane damage (leakage of aspartate aminotransferase), by the lessening of the Cd2(+)-stimulated lipid peroxidation (TBA-reactants) and by the increase in Cd2(+)-depleted cellular glutathione (GSH + 2 GSSG). Half-maximal protection was achieved at molar ratios of 9.9 to 19 (lipoate vs. Cd2+) and 0.25 to 0.74 (dihydrolipoate vs. Cd2+), indicating a 19.5 to 50.6 lower protective efficacy of lipoate as compared to dihydrolipoate. Lipoate induced an increase in extracellular acid-soluble thiols different from glutathione. It is suggested that dihydrolipoate primarily protects cells by extracellular chelation of Cd2+, whereas intracellular reduction of lipoate to the dihydro-compound followed by complexation of both intra- and extracellular Cd2+ contributes to the amelioration provided by lipoate.

Biochim Biophys Acta. 1990 May 22;1052(3):386-91

Protective role of DL-alpha-lipoic acid against mercury-induced neural lipid peroxidation.

Experimental neurotoxicity in rat models was induced by an intramuscular injection of mercuric chloride. dl-alpha-lipoic acid was administered as an antidote in three protocols of experimental design. Two protocols of short-term exposure of mercury was designed, one with prophylactic therapy and the other with curative therapy of lipoic acid. The third protocol was with prophylactic therapy of lipoic acid on long-term exposure of mercury. Enhanced lipid peroxidation, depleted non-enzymic and perturbed enzymic antioxidant status were observed in cerebral cortex, cerebellum and sciatic nerves of the toxic groups. The ameliorating effect of lipoic acid and its therapeutic efficacy during various modes of therapy, on the antioxidant status was established in the nervous tissues.

Pharmacol Res. 1999 Jan;39(1):67-80