Tardive dyskinesia

Melatonin effective against tardive dyskinesia

Twenty-two patients with schizophrenia and tardive dyskinesia were randomly assigned to receive, in double-blind fashion, 10mg of melatonin or placebo each night at 8 p.m. for six weeks. After a 4-week washout period they received the alternate treatment for an additional six weeks. The mean Abnormal Involuntary Movement Scale score (a measure of the severity of tardive dyskinesia) decreased (improved) by 23.8% during melatonin treatment and by 8.4% during placebo treatment (p < 0.001 for the difference in the change between groups). No adverse effects were seen.

Comment: This study demonstrates that melatonin is an effective treatment for tardive dyskinesia, although the magnitude of the effect appears to be modest. This common drug-induced movement disorder appears to be caused in part by increased sensitivity of the dopamine receptor, as well as increased oxidative stress, in the nigrostriatal system of the brain. Melatonin is a potent antioxidant; it also attenuates dopaminergic activity in the striatum and dopamine release from the hypothalamus. Thus, melatonin may influence tardive dyskinesia by two separate mechanisms. Other natural substances that have been reported to improve tardive dyskinesia include vitamin E, manganese, and vitamin B6. It is possible that using these compounds in combination would be more effective than using any one individually; however, additional research is needed to confirm that possibility.

Shamir E, et al. Melatonin treatment for tardive dyskinesia. A double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry 2001;58:1049-1052.

Melatonin for epilepsy

Six children (aged 2-15 years) with severe intractable seizures were treated with 3 mg of oral melatonin 30 minutes before bedtime, in addition to their usual anti-seizure medication, for three months. Five of the six children experienced a reduction in seizure activity, particularly dining the night, beginning three days after the start of treatment. The mean seizure rate decreased from 3.6 per day at baseline to 1.5 per day during treatment (58% reduction; p < 0.05). Daytime behavior also improved, according to parental reports.

Comment: This preliminary study suggests that melatonin has anticonvulsant activity and may be useful in difficult-to-treat cases of epilepsy. However, in a previous study, administration of melatonin to epileptic children as a treatment for insomnia resulted in an increase in seizure activity in some cases. Thus, while a therapeutic trial of melatonin may be reasonable for children with intractable seizures, its use should be monitored closely.

Peled N, et al. Melatonin effect on seizures in children with severe neurologic deficit disorders. Epilepsia 2001;42:1208-1210.

Estriol for menopausal symptoms

Twenty-eight postmenopausal women (mean age, 56.5 years; range, 47-74 years) with urogenital symptoms (dysuria, urinary frequency, stress incontinence, vaginal burning, vaginal dryness, and dyspareunia) received 2 mg/day of oral estriol for 12 weeks. Significant improvements were seen in dysuria, urinary frequency, and stress incontinence after 12 weeks (p < 0.05 for each). Vaginal burning,, vaginal dryness, and dyspareunia all improved significantly within four weeks. The mean plasma estradiol concentration increased from 17.5 pg/ml at baseline to 26.8 pg/ml after 12 weeks (p < 0.05), whereas the mean FSH concentration did not change significantly (small increase). Vaginal cytology showed an estrogenic effect on the karyopyknotic index and maturation value.

Comment: This study showed that oral administration of a relatively small dose of estriol had a positive effect on urogenital symptoms and vaginal cytology in postmenopausal women. Estriol is one of the three naturally occurring estrogens in the human body (the other two are estrone and estradiol). Interest in using estriol for hormone-replacement therapy has been stimulated by the observation that this hormone, in contrast with conventional estrogen therapy, rarely induces endometrial hyperplasia, and may not have an adverse effect on breast-cancer risk. One of the main reasons estriol has not been used more often (aside from the usual drags of inertia and financial conflicts of interest) is that doctors have not been convinced of its efficacy. This study, combined with reports that estriol is effective against osteoporosis (see below), provide a strong rationale for the use of estriol (either alone or in combination with small amounts of estrone and/or estradiol) as an alternative to conjugated equine estr ogens (Premarin) or pure estradiol (Estrace).

Manonai J, et al. Effect of oral estriol on urogenital symptoms, vaginal cytology, and plasma hormone level in postmenopausal women. J Med Assoc Thai 2001;84:539-544.

Estriol prevents postmenopausal osteoporosis

Seventy-five women (mean age, 53.1 years) who had undergone natural menopause and whose bone mineral density (BMD) of the lumbar spine was more than 10% below the peak bone density received 2 mg/day of estriol for 50 weeks. The estriol was given cyclically: 4 weeks on, 1 week off. Each woman also received 104 mg/day of supplemental calcium (from calcium lactate). The mean BMD of the lumbar spine (measured by dual energy X-ray absorptiometry) increased by 1.79% (p < 0.01 compared with baseline) after 50 weeks, accompanied by a decrease of biochemical markers of bone turnover (e.g., serum alkaline phosphatase and urinary excretion of deoxypyridinoline). The increase in BMD was greatest in women who had entered menopause at least 5 years previously; in the women with a shorter duration of menopause, the increase in BMD was not statistically significant. Menopausal symptoms (as determined by Kupperman's index) improved significantly (p < 0.01) after 5 weeks of treatment. Vaginal bleeding occurred in 8% of the wo men. Endometrial smears and biopsies, performed before and after 25 and 50 weeks of treatment, showed no endometrial hyperplasia or other abnormalities.

Comment: This study is one of several that have shown that estriol can halt or reverse bone loss in postmenopausal women. In addition, during the one-year study, estriol improved menopausal symptoms, but did not induce endometrial hyperplasia. The best way to administer estriol (e.g., continuously or cyclically; alone or in combination with estrone/estradiol) has not been systematically studied. Considering the potential advantages of estriol over conventional estrogen-replacement therapy, such research is urgently needed. Preliminary evidence suggests that cyclical administration of estriol is preferable to continuous administration, in terms of further reducing the small risk of endometrial hyperplasia.

Minaguchi H, et al. Effect of estriol on bone loss in postmenopausal Japanese women: a multicenter prospective open study. J Obstet Gynaccol Res 1996;22:259-265.

Licorice does not lower testosterone levels

In a previous Townsend Letter column, I reviewed a report in the New England Journal of Medicine (1999;341:1158) demonstrating that ingestion of licorice by healthy young males reduced serum testosterone concentrations by an average of 34%. This effect was attributed to an inhibition of enzymes involved in testosterone synthesis. However, a new study in Lancet has failed to confirm the initial report. In the new study, ingestion of licorice by healthy young men, in amounts similar to those used in the first study, resulted in only a 9.5% reduction in testosterone levels (measured in saliva), and this reduction was not statistically significant. Salivary and serum testosterone concentrations are known to be very strongly correlated, so the difference in results does not seem to be attributable to a difference in methodology. Statistical analysis of the original report revealed that at least one of the participants apparently had an initial testosterone concentration that was substantially higher than the mean. Removal of this statistical outlier would presumably have reduced the magnitude of the reported effect.

Comment: If licorice does reduce testosterone concentrations, the effect appears to be smaller than that previously reported. Nevertheless, doctors should continue to question patients about licorice ingestion if they present with reduced libido or other evidence of testosterone deficiency.

Josephs RA, et al. Liquorice consumption and salivary testosterone concentrations Lancet 2001;358:1613-1614.

Thyroid hormone for chronic hives

Ten euthyroid patients with chronic refractory hives were treated with thyroxine for a minimum of 12 weeks. The initial dose was 0.025-0.1 mg/day (mostly 0.1 mg/day), depending on age and medical condition; this was increased if the initial dose failed to produce a clinical response. Of seven patients with elevated anti-thyroid antibodies (e.g., anti-thyroglobulin and/or anti-microsomal antibodies) at baseline, all seven had complete resolution of hives or marked improvement within four weeks. Two patients required an increase in the thyroxine dose before complete resolution was seen; in two others who were already on thyroxine therapy for hypothyroidism, an increase in the dose resulted in resolution of symptoms. The highest dose used was 0.25mg/day. The three patients without elevated anti-thyroid antibodies did not respond. Five patients had a recurrence of symptoms after treatment was stopped; these symptoms resolved again after treatment was restarted. There was no consistent correlation between improvem ent in symptoms and reduction in thyroid antibody titers.

Comment: This study suggests that thyroid autoimmunity is common in euthyroid patients with chronic urticaria. Furthermore, administration of thyroxine to pa patients with chronic urticaria associated with elevated thyroid antibodies can result in remission of the hives. The mechanism by which thyroid hormone improves chronic urticaria in these patients is not clear. It should be noted that many commercially available thyroxine preparations are colored with coal-tar dyes. For example, the 0.1-mg dose of Synthroid contains tartrazine (FD&C Yellow #5), which is a known cause of urticaria. The 0.05-mg tablet, on the other hand, is free of colorants. Therefore, for patients with chronic urticaria who are sensitive to coal-tar dyes, one might either 1) prescribe one or more tablets of the 0.05-mg strength, 2) obtain the thyroxine from a compounding pharmacist, or 3) consider the use of desiccated thyroid.

Rumbyrt JS, et al. Resolution of chronic urticaria in patients with thyroid autoimmunity. J Allergy Clin Immunol 1995;96:901-905.

DHEA may prevent heart disease in postmenopausal women

Twenty healthy postmenopausal women (mean age, 56 years) who were androgen-deficient (defined as serum DHEAS concentration less than 2.5 micromol/L) were randomly assigned to receive 25 mg/day of DHEA or placebo for 12 months. After 12 months, compared with baseline, the DHEA group showed a significant improvement in insulin sensitivity (determined by euglycemic hyperinsulinemic clamp; p = 0.01). In addition, the mean LDL cholesterol concentration fell by 11.1% (p = 0.04), HDL cholesterol increased by 11.6% (p = 0.03), and triglycerides fell by 19.6% (p = 0.03). There were no significant changes and no favorable trends in these parameters in the placebo group.

Comment: In this study, supplementation of androgen-deficiency postmenopausal women with DHEA resulted in an improvement in glucose metabolism and lipid levels; changes that would be expected to prevent the development of cardiovascular disease. These findings suggest that a postmenopausal decline in DHEA levels may play a role in the increased cardiovascular risk that is associated with the onset of menopause. However, as the current study used only women who had initially low DHEAS concentrations, it is not clear whether the same benefits would be seen among women with normal or high DHEAS levels. In fact, epidemiological studies have shown that high concentrations of DHEAS are associated with higher cardiovascular risk among women. Therefore, DHEA replacement therapy may be appropriate only for women whose serum levels of DHEAS are below normal or in the low-normal range for young women.

Lasco A, Frisina N, Morabito N, Gaudio A, Morini E, Trifiletti A, et al. Metabolic effects of dehydroepiandrosterone replacement therapy in postmenopausal women. Eur J Endocrinol 2001;145:457-461.

Antiinflammatory effect of olive oil

Supplementation of the diet of rats with virgin olive oil (15% of the diet) resulted in an antiinflammatory effect in the carrageenan edema test. The effect was greater than that resulting from supplementation with high-oleic-acid sunflower oil. Enrichment of virgin olive oil with its polyphenolic fraction, to approximate the higher polyphenolic content of extra-virgin olive oil, resulted in a greater antiinflammatory effect than that seen with virgin olive oil. In established adjuvant arthritis, the polyphenolic-enriched virgin olive oil was even more effective than fish oil in preventing inflammation. Both polyphenolic-enriched virgin olive oil and fish oil enhanced the antiinflammatory effect of indomethacin.

Comment: This study suggests that olive oil has antiinflammatory activity and that the effect is due largely to the polyphenolic compounds it contains, although oleic acid may also contribute to the effect. Because of its higher polyphenolic content, extra-virgin olive oil is a more potent antiinflammatory agent than is virgin olive oil. The use of extra-virgin olive oil may therefore be considered as part of the overall treatment of various inflammatory conditions. It is noteworthy that some previous studies that have assessed the effect of fish oil or other oils in the treatment of arthritis have used olive oil as the "placebo." Because olive oil is not an inert placebo, the beneficial effect of the other oils being tested may have been underestimated.

Martinez-Dominguez E, et al. Protective effects upon experimental inflammation models of a polyphenol-supplemented virgin olive oil diet.

Inflamm Res 2001;50:102-106.

COPYRIGHT 2002 The Townsend Letter Group
COPYRIGHT 2002 Gale Group