Literature Review and Commentary

By Alan R. Gaby, MD

Carotenoids Play a Role in Cognitive Function

Ninety-one healthy individuals (mean age, 45 years) with low concentrations of macular pigment were randomly assigned to receive, in double-blind fashion, a daily supplement containing 10 mg of lutein, 10 mg of meso-zeaxanthin, and 2 mg of zeaxanthin or placebo for 12 months. Compared with placebo, supplementation with the carotenoids resulted in significant improvements in scores on four tests that measured memory function out of a total of seven tests that measured cognitive function.

Comment: Lutein and zeaxanthin are dietary carotenoids that have been shown to prevent age-related macular degeneration. The beneficial effect of these carotenoids in the retina appears to result from their capacity to filter the phototoxic blue-light portion of the sun’s rays. Lutein and zeaxanthin have also been identified in the hippocampus, cerebellum, and frontal, occipital, and temporal cortices of the human brain. The concentrations of these carotenoids in the brain correlate with their respective concentrations in the retina. The results of the present study indicate that the combination of lutein, zeaxanthin, and meso-zeaxanthin can improve memory in healthy individuals with presumed suboptimal intake of lutein and zeaxanthin (as suggested by low concentrations of these carotenoids in macular pigment). The supplement used in this study also contained meso-zeaxanthin, which is not a major dietary carotenoid, but which can be synthesized in the retina from lutein. To what extent, if any, the improvement in cognitive function observed in the present study was due to meso-zeaxanthin was not investigated.

Power R, et al. Supplemental retinal carotenoids enhance memory in healthy individuals with low levels of macular pigment in a randomized, double-blind, placebo-controlled clinical trial. J Alzheimers Dis. 2018;61:947-961.

Wernicke’s Encephalopathy: Both Thiamine and Magnesium Are Important

A 34-year-old male developed signs of Wernicke’s encephalopathy that failed to respond to high-dose intravenous thiamine. Serum magnesium was found to be below normal. Intravenous administration of both magnesium and thiamine resulted in a resolution of symptoms after his serum magnesium level became normal.

Comment: Wernicke’s encephalopathy is a neuropsychiatric disorder that results primarily from thiamine deficiency. The condition is common among chronic alcoholics and has also been observed in people with persistent vomiting (including hyperemesis gravidarum), advanced cancer (particularly in patients who have had surgery for gastrointestinal cancer), Crohn’s disease, or a history of bariatric surgery.

Magnesium is required for the conversion of thiamine to its biologically active form.¹ Furthermore, some thiamine-dependent enzymes also require magnesium. In patients who are deficient in both thiamine and magnesium, symptoms of thiamine deficiency may not respond to thiamine supplementation unless magnesium deficiency is also corrected. In addition, administration of large doses of thiamine can exacerbate magnesium deficiency. Magnesium supplementation should therefore be considered for patients being treated with thiamine.

Coughlan JJ, et al. Thiamine refractory Wernickes encephalopathy reversed with magnesium therapy. BMJ Case Rep. 2016;2016:bcr2016218046.

Fatty Acids Improve Reading Ability in Children

One hundred fifty-four children (aged 9-10 years) in Sweden were randomly assigned to receive, in double-blind fashion, three capsules twice a day of omega-6 and omega-3 fatty acids or placebo (palm oil) for three months. The active treatment provided daily 558 mg of eicosapentaenoic acid, 174 mg of docosahexaenoic acid, and 60 mg of gamma-linolenic acid. One hundred twenty-two children completed the trial. In both intent-to-treat and per-protocol analysis, active treatment was superior to placebo for improvement in phonologic decoding time and visual analysis time. For children with ADHD-Rating-Scale-IV scores above the median (indicating more attention deficit-hyperactivity disorder [ADHD] symptoms), compared with placebo, active treatment improved visual analysis time (p < 0.01), reading speed (p < 0.01), and phonologic decoding time (p = 0.006).

Comment: The results of this study indicate that supplementation with the combination of eicosapentaenoic acid, docosahexaenoic acid, and gamma-linolenic acid improved certain parameters of reading ability in schoolchildren in Sweden, particularly those with attention problems. In previous uncontrolled² and two double-blind trials,^3,4 supplementation with docosahexaenoic acid or with a combination of fish oil and evening primrose oil (which contains gamma-linolenic acid) improved reading skills in children with dyslexia. Additional research is needed to determine which regimen of fatty acids is most effective and which children are most likely to benefit.

Johnson M, et al. Omega 3/6 fatty acids for reading in children: a randomized, double-blind, placebo-controlled trial in 9-year-old mainstream schoolchildren in Sweden. J Child Psychol Psychiatry. 2017;58:83-93.

Biotin and Multiple Sclerosis

Forty-three patients (median age, 61 years) with progressive multiple sclerosis (median disease duration, 23 years; 26 secondary progressive, 7 primary progressive, 10 relapsing remitting with progression) were asked to take 300 mg of biotin once a day for at least one year. Twenty patients were on disease-modifying drugs and continued those drugs during biotin treatment. Twenty-four patients completed one or more years of biotin treatment. Discontinuation of biotin was almost always due to lack of perceived benefit or perceived worsening of symptoms. High-dose biotin was safe and well tolerated, and no new lesions were seen on brain MRIs. None of the patients improved according to the Expanded Disability Status score (EDSS). Some 38-43% of the patients became worse, most often with increased lower extremity weakness, worse balance, and more falling. Several patients who had become worse while taking biotin improved after stopping it.

Comment: Biotin is a cofactor for acetyl-CoA carboxylase, a potentially rate-limiting enzyme in myelin synthesis. In a previous uncontrolled trial, 90% of 23 patients with multiple sclerosis (primary or secondary progressive) experienced various neurological improvements while taking biotin (100-300 mg per day for a mean duration of 9 months).⁵ However, in a follow-up double-blind trial, high-dose biotin (300 mg per day for 1 year) produced clinical improvement in only 13% of patients.⁶ In the new study, biotin treatment was not beneficial. As compared with the other trials of high-dose biotin for multiple sclerosis, the patients in the present study were older, had longer disease duration, and were more disabled.

Despite its uncertain efficacy, biotin is safe and relatively inexpensive, so a clinical trial in selected patients with multiple sclerosis seems reasonable. Supplementation with large doses of biotin may interfere with laboratory tests for vitamin B₁₂, certain steroid hormones, and thyroid function (potentially leading to an erroneous diagnosis of Graves’ disease). It has been recommended that people taking high-dose biotin discontinue it for 72 hours before having blood tests.

Birnbaum G, Stulc J. High dose biotin as treatment for progressive multiple sclerosis. Mult Scler Relat Disord. 2017;18:141-143.

Alpha-Lipoic Acid for Schizophrenia

Twelve Brazilian patients (aged 18-60 years; mean age, 38.5 years) with chronic schizophrenia (mean disease duration, 18.7 years) who had been on stable doses of antipsychotic medication for at least one year received 100 mg per day of alpha-lipoic acid (ALA) in open-label fashion for four months. Ten patients completed the trial. All patients improved; the mean improvement in the Brief Psychiatric Rating Scale (BPRS) score was 63.9%. All domains of the BPRS showed improvement in the mean score (percent improvement in parentheses): negative symptoms/disorganization (69%), excitement (76%), depressive symptoms (47%), and positive symptoms (52%). A significant improvement in extrapyramidal symptoms was also seen.

Comment: The authors of this report cited two studies from the 1950s in which ALA improved symptoms in at least half of patients with schizophrenia. In those studies, two of three patients who improved on a dose of 100 mg per day deteriorated when the dose was increased to 200 mg per day. In more recent studies, ALA at a dose of 300 or 1,200 mg per day did not improve symptoms in patients with schizophrenia. Taken together, these findings raise the possibility that there is a “therapeutic window” for ALA in the treatment of schizophrenia, such that doses either above or below the therapeutic window are less effective than the optimal dose. Additional controlled trials are needed to investigate that possibility.

Sanders LLO, et al. Alpha-lipoic acid as adjunctive treatment for schizophrenia: an open-label trial. J Clin Psychopharmacol. 2017;37:697-701.

Vitamin B3 for Bipolar Disorder

A 60-year-old man had a long history of bipolar disorder that had been treated with lithium and other psychotropic medications. These medications had had beneficial effects but at times were insufficient. The man was prescribed sustained-release niacin at a dose of 1 g twice a day to treat anxiety. He experienced a marked improvement in both anxiety and depression and was able to wean off all psychotropic medication over a period of about one year. The patient has remained well for 11 years while taking niacin, currently 1 g three times per day of the regular-release form. On a few occasions, discontinuation of niacin resulted in a return of anxiety and depression within two to three days, which again resolved within one day of resuming niacin.

Comment: Vitamin B3 (niacin or niacinamide) plays a role in serotonin metabolism, and has been reported in uncontrolled trials to be of value in the treatment of depression, anxiety, and insomnia. This case report suggests that vitamin B3 is also useful for selected patients with bipolar disorder. The authors of the report suggested that this patient had a vitamin dependency (i.e., an unusually large requirement for vitamin B3, possibly genetically determined). The patient had a strong family history of depression and other psychiatric disorders, and it would be interesting to determine whether other family members would have a positive response to niacin or niacinamide.

Jonsson BH. Nicotinic acid long-term effectiveness in a patient with bipolar type II disorder: A case of vitamin dependency. Nutrients. 2018;10:E134.

Subtle Hypothyroidism and Infertility

A cross-sectional study was conducted on 239 infertile couples in which the female partner had a normal thyroid-stimulating hormone (TSH) level. One hundred eighty-seven women (mean age 31.5 years) had unexplained infertility and 52 women (control group) (mean age, 30.1 years) had no other cause of infertility than a partner with sperm abnormalities (azoospermia or severe oligospermia). The median TSH level was significantly higher in the women with unexplained infertility than in the control group (1.95 vs. 1.66 mIU/L; p = 0.003). The proportion of women who had a TSH level of 2.5 mIU/L or greater was significantly higher in the women with unexplained infertility than in the control group (26.9% vs. 13.5%; p = 0.003).

Comment: Hypothyroidism is a known cause of infertility. In the present study, unexplained infertility in women was associated with higher TSH levels in the normal range. That finding raises the possibility that some women with unexplained infertility have subtle hypothyroidism. In my experience, some infertile women have normal thyroid-function tests but clinical evidence of possible hypothyroidism (e.g., cold extremities, fatigue, depression, edema, constipation, delayed Achilles tendon reflex return). In many of these women, a clinical trial of low-dose thyroid hormone is followed by an improvement in the various signs and symptoms and a successful pregnancy. The evaluation and management of “sub-laboratory” hypothyroidism has been discussed elsewhere.^7,8

Orouji Jokar T, et al. Higher TSH levels within the normal range are associated with unexplained infertility. J Clin Endocrinol Metab. 2018;103:632-639.

Tea and Iron Absorption: Timing Matters

Twelve iron-replete non-anemic women (mean age, 25 years) consumed a standardized porridge meal extrinsically labeled with ⁵⁷Fe as ferrous sulfate on three separate occasions, with a 14-day interval between each test meal. The meal was administered with water during the first test, with 200 ml of black tea consumed simultaneously with the meal during the second test, and with 200 ml of tea consumed one hour after the meal during the third test. Fractional iron absorption was 5.7% with the water test, 3.6% with simultaneous tea ingestion (37% inhibition), and 5.7% when tea was ingested one hour after the meal (p < 0.05 comparing simultaneous tea ingestion and 1-hour postprandial tea ingestion).

Comment: Black tea (and, to a lesser extent, green tea) has been shown to inhibit nonheme iron absorption, but it has not been clear whether the timing of tea consumption relative to a meal influences iron bioavailability. The results of the present study indicate that the inhibitory effect of black tea on nonheme iron absorption can be prevented by consuming the tea one hour after the meal.

Ahmad Fuzi SF, et al. A 1-h time interval between a meal containing iron and consumption of tea attenuates the inhibitory effects on iron absorption: a controlled trial in a cohort of healthy UK women using a stable iron isotope. Am J Clin Nutr. 2017;106:1413-1421.