Nutritional and Hormonal Therapies for Depression and Anxiety: Selected Abstracts

ST. JOHN’S WORT: Despite a few negative trials, the large majority of studies show that St. John’s is effective for mild and moderate depression. Toxicity is very low, except for sunburn. However, there are substantial potential drug interactions, including, possibly with birth control pills. Don’t mix with tryptophan or with SSRI’s.

1: Psychopharmacology (Berl) 2002 Nov;164(3):294-300

St John's wort extract (LI 160) in somatoform disorders: results of a placebo-controlled trial. Volz HP, Murck H, Kasper S, Moller HJ.

Psychiatric Department, University of Jena, Philosophenweg 3, 07740 Jena, Germany, volz.werneck@t-online.de

2:  JAMA 2002 Apr 10;287(14):1807-14

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial.

Hypericum Depression Trial Study Group.

Richard Podell, M.D. Lecture on Natural Treatments for Anxiety and Depression, December 18, 2002 to the faculty and residents of the

Department of Family Medicine, University of Medicine and Dentistry

Of New Jersey—Camden Campus

Please Note: These recent references have been taken from the scientific data base of the National Library of Medicine

 Am J Psychiatry 2002 Aug;159(8):1361-6

Efficacy of St. John's Wort extract WS 5570 in major depression: a double-blind, placebo-controlled trial. Lecrubier Y, Clerc G, Didi R, Kieser M.

Unite Institut National de la Sante et de la Recherche Medicale 302, Hopital Pitie Salpetriere, Paris, France. lecru@ext.jussieu.fr

OBJECTIVE: In a double-blind, randomized, placebo-controlled trial with 375 patients the authors investigated the antidepressant efficacy and safety of 300 mg t.i.d. of hydroalcoholic Hypericum perforatum extract WS 5570. METHOD: The study participants were male and female adult outpatients with mild to moderate major depression (single or recurrent episode, DSM-IV criteria). After a single-blind placebo run-in phase, the patients were randomly assigned, 186 to WS 5570 and 189 to placebo, after which they received double-blind treatment for 6 weeks. Follow-up visits were held after 1, 2, 4, and 6 weeks. The primary outcome measure was the change from baseline in the total score on the 17-item Hamilton Depression Rating Scale. In addition, analyses of responders (patients with at least a 50% reduction in Hamilton total score) and patients with remissions (patients with a total score of 6 or less on the Hamilton scale at treatment end) were carried out, and subscale/subgroup analyses were conducted. The design included an adaptive interim analysis performed after random assignment of 169 patients with options for group size adjustment or early termination. RESULTS: Compared to placebo, WS 5570 produced a significantly greater reduction in total score on the Hamilton depression scale and significantly more patients with treatment response or remission. It was more effective in patients with higher baseline Hamilton scores and led to global reduction of depression-related core symptoms, assessed with the melancholia subscale of the Hamilton scale. The placebo and WS 5570 groups had comparable adverse events.

CONCLUSIONS: H. perforatum extract WS 5570 was found to be safe and more effective than placebo for the treatment of mild to moderate depression.

1: Can Fam Physician 2002 May;48:905-12

St John's wort or sertraline? Randomized controlled trial in primary care. van Gurp G, Meterissian GB, Haiek LN, McCusker J, Bellavance F.

Emergency Department, St Mary's Hospital Centre, 3830 Lacombe Ave, Montreal, QC. gerald.vangurp@mcgill.ca

OBJECTIVE: To compare the change in severity of depressive symptoms and occurrence of side effects in primary care patients treated with St John's wort (SJW) and sertraline. DESIGN: Double-blind, randomized 12-week trial. SETTING: Community-based offices of 12 family physicians practising in greater Montreal, Que. PARTICIPANTS: Eighty-seven men and women with major depression and an initial score of > or = 16 on the Hamilton Rating Scale for Depression (Ham-D). INTERVENTIONS: Patients were randomized to treatment with either sertraline (50 to 100 mg/d) or SJW (900 to 1800 mg/d) in a double-blind fashion. Assessment of depression was done at entry and at 2, 4, 8, and 12 weeks using the Ham-D, the Beck Depression Inventory (BDI), and a questionnaire asking about compliance and side effects. MAIN OUTCOME MEASURES: Changes from baseline in Ham-D and BDI scores and self-reported side effects. RESULTS: There were no important differences in changes in mean Ham-D and BDI scores (using intention-to-treat analysis), with and without adjustment for baseline demographic characteristics, between the two groups at 12 weeks. Significantly more side effects were reported in the sertraline group than in the SJW group at 2 and 4 weeks' follow up. CONCLUSION: The more benign side effects of SJW make it a good first choice for this patient population.

1: Adv Ther 2002 Jan-Feb;19(1):43-52

Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Behnke K, Jensen GS, Graubaum HJ, Gruenwald J.

PhytoPharm Consulting, Institute for Phytopharmaceuticals, Berlin, Germany.

In a randomized, controlled, double-blind trial, 70 patients (mean age, 49.7 years) suffering from mild to moderate depression received one tablet of either St. John's Wort (Hypericum perforatum) extract (Calmigen) or fluoxetine hydrochloride (Prozac) twice a day for 6 weeks. Efficacy was determined according to the 17-item Hamilton Rating Scale for Depression (HAMD), the von Zerssen depression scale (DS), Clinical Global Impression (CGI), and patients' overall evaluation. Significant decreases (P<.001) of 50% in the Hypericum group and 58% in the fluoxetine group in the HAMD score and of 42% and 52% on the DS spoke to the efficacy of both medications. The Hypericum extract achieved 83% of the efficacy of fluoxetine on the HAMD and 78% on the DS. Assessments by physicians (CGI) and patients indicated considerable improvement with no between-treatment differences. Of the 9 dropouts (13%), 2 in the Hypericum group and 2 in the fluoxetine group were due to adverse reactions. Safety evaluations demonstrated only minor changes. The Hypericum preparation tested in this study is therapeutically equivalent to fluoxetine and is therefore a rational alternative to synthetic antidepressants.

 JAMA 2002 Apr 10;287(14):1807-14

Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial. Hypericum Depression Trial Study Group.

CONTEXT: Extracts of Hypericum perforatum (St John's wort) are widely used for the treatment of depression of varying severity. Their efficacy in major depressive disorder, however, has not been conclusively demonstrated. OBJECTIVE: To test the efficacy and safety of a well-characterized H perforatum extract (LI-160) in major depressive disorder. DESIGN AND SETTING: Double-blind, randomized, placebo-controlled trial conducted in 12 academic and community psychiatric research clinics in the United States. PARTICIPANTS: Adult outpatients (n = 340) recruited between December 1998 and June 2000 with major depression and a baseline total score on the Hamilton Depression Scale (HAM-D) of at least 20. INTERVENTIONS: Patients were randomly assigned to receive H perforatum, placebo, or sertraline (as an active comparator) for 8 weeks. Based on clinical response, the daily dose of H perforatum could range from 900 to 1500 mg and that of sertraline from 50 to 100 mg. Responders at week 8 could continue blinded treatment for another 18 weeks. MAIN OUTCOME MEASURES: Change in the HAM-D total score from baseline to 8 weeks; rates of full response, determined by the HAM-D and Clinical Global Impressions (CGI) scores. RESULTS: On the 2 primary outcome measures, neither sertraline nor H perforatum was significantly different from placebo. The random regression parameter estimate for mean (SE) change in HAM-D total score from baseline to week 8 (with a greater decline indicating more improvement) was -9.20 (0.67) (95% confidence interval [CI], -10.51 to -7.89) for placebo vs -8.68 (0.68) (95% CI, -10.01 to -7.35) for H perforatum (P =.59) and -10.53 (0.72) (95% CI, -11.94 to -9.12) for sertraline (P =.18). Full response occurred in 31.9% of the placebo-treated patients vs 23.9% of the H perforatum-treated patients (P =.21) and 24.8% of sertraline-treated patients (P =.26). Sertraline was better than placebo on the CGI improvement scale (P =.02), which was a secondary measure in this study. Adverse-effect profiles for H perforatum and sertraline differed relative to placebo.

CONCLUSION: This study fails to support the efficacy of H perforatum in moderately severe major depression. The result may be due to low assay sensitivity of the trial, but the complete absence of trends suggestive of efficacy for H perforatum is noteworthy.

Comment: This is the main negative result study, which shows St. John’s not as good as placebo. However, Zoloft, while somewhat better than St. John’s in this trial, was also inferior to placdbo. Go figure.

Xenobiotica 2002 Jun;32(6):451-78

Pharmacokinetic interactions between herbal remedies and medicinal drugs. Ioannides C.

Molecular Toxicology Group, School of Biomedical and Life Sciences, University of Surrey, Guildford GU2 7XH, UK. c.ioannides@surrey.ac.uk

1. The use of herbal products to treat a wide range of conditions is rising rapidly, leading to increased intake of phytochemicals. Recent studies revealed potentially fatal interactions between herbal remedies and traditional drugs. 2. In transplant patients, self-medication with St John's wort (Hypericum perforatum) has led to a drop in plasma levels of the immunosuppressant drug cyclosporine, causing tissue rejection. 3. Intake of St John's wort increases the expression of intestinal P-glycoprotein and the expression of CYP3A4 in the liver and intestine. The combined up-regulation in intestinal P-glycoprotein and hepatic and intestinal CYP3A4 impairs the absorption and stimulates the metabolism of cyclosporine, leading to subtherapeutic plasma levels. The St John's wort component, hyperforin, contributes to the induction of CYP3A4. 4. St John's wort also enhances the metabolism of other CYP3A4 substrates including the protease inhibitors indinavir and nevirapine, oral contraceptives, and tricyclic antidepressants such as amitriptyline. 5. Other herbal remedies with the potential to modulate cytochrome P450 activity and thus participate in interactions with conventional drugs include Milk thistle, Angelica dahurica, ginseng, garlic preparations, Danshen and liquorice. 6. Herbal products are currently not subject to the rigorous testing indispensable for conventional drugs. However, if potential drug interactions are to be predicted, it is essential that the ability of herbal products to interfere with drug-metabolizing enzyme systems is fully established.

Comment: St. John’s speeds up various liver enzyme systems. Hence the potential for increasing metabolic decay for various drugs.

S-Adenosyl Methionine (SAM-E)

SAM-e has strong data favoring effectiveness. However, I’ve found it to have initial hyper stimulating side-effects similar to those found with Prozac. On the other hand, I have a few patients who have not tolerated any medicine for depression who did tolerate SAMe. The main issue is that we have no long term data. What happens if you flood the brain with supraphysiological doses of SAMe for a year or two? (Same question of course for Prozac.)

SAMe is the most important methyl donor molecule in the brain. It is necessary for the synthesis of many neurochemicals.

 Am J Clin Nutr 2002 Nov;76(5):1158S-61S  

Role of S-adenosyl-L-methionine in the treatment of depression: a review of the evidence. Mischoulon D, Fava M.

Harvard Medical School, Depression Clinical and Research Program, Massachusetts General Hospital, Boston 02114, USA. dmischoulon@partners.org

Major depression remains difficult to treat, despite the wide array of registered antidepressants available. In recent years there has been a surge in the popularity of natural or alternative medications. Despite this growing popularity, there is limited evidence for the effectiveness of many of these natural treatments. S-adenosyl-L-methionine (SAMe) is one of the better studied of the natural remedies. SAMe is a methyl donor and is involved in the synthesis of various neurotransmitters in the brain. Derived from the amino acid L-methionine through a metabolic pathway called the one-carbon cycle, SAMe has been postulated to have antidepressant properties. A small number of clinical trials with parenteral or oral SAMe have shown that, at doses of 200-1600 mg/d, SAMe is superior to placebo and is as effective as tricyclic antidepressants in alleviating depression, although some individuals may require higher doses. SAMe may have a faster onset of action than do conventional antidepressants and may potentiate the effect of tricyclic antidepressants. SAMe may also protect against the deleterious effects of Alzheimer disease. SAMe is well tolerated and relatively free of adverse effects, although some cases of mania have been reported in bipolar patients. Overall, SAMe appears to be safe and effective in the treatment of depression, but more research is needed to determine optimal doses. Head-to-head comparisons with newer antidepressants should help to clarify SAMe's place in the psychopharmacologic armamentarium.

FOLIC ACID

There are strong theoretical and fair empirical reasons to believe that optimizing folic acid, B 12 metabolism helps depression. Note homocysteine requires B12 and Folic Acid to form Methionine, which then forms S-Adenosyl Methionine (SAMe)

I suggest measuring homocysteine and methyl malonic acid as functional tests of folic and B 12 metabolism, seeking not absence of deficiency but optimization e.g. aim for homocysteine 4-8, and give what it takes.

1: J Affect Disord 2000 Nov;60(2):121-30

Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. Coppen A, Bailey J.

MRC Neuropsychiatry Laboratory, West Park Hospital, KT19 8PB, Surrey, Epsom, UK.

BACKGROUND: A consistent finding in major depression has been a low plasma and red cell folate which has also been linked to poor response to antidepressants. The present investigation was designed to investigate whether the co-administration of folic acid would enhance the antidepressant action of fluoxetine. METHODS: 127 patients were randomly assigned to receive either 500 microg folic acid or an identical looking placebo in addition to 20 mg fluoxetine daily. All patients met the DSM-III-R criteria for major depression and had a baseline Hamilton Rating Scale (17 item version) score for depression of 20 or more. Baseline and 10-week estimations of plasma folate and homocysteine were carried out. RESULTS: Patients receiving folate showed a significant increase in plasma folate.This was less in men than in women. Plasma homocysteine was significantly decreased in women by 20.6%, but there was no significant change in men. Overall there was a significantly greater improvement in the fluoxetine plus folic acid group. This was confined to women where the mean Hamilton Rating Scale score on completion was 6.8 (S.D. 4. 1) in the fluoxetine plus folate group, as compared to 11.7 (S.D. 6. 7) in the fluoxetine plus placebo group (P<0.001).A percentage of 93. 9 of women, who received the folic acid supplement, showed a good response (>50% reduction in score) as compared to 61.1% of women who received placebo supplement (P<0.005). Eight (12.9%) patients in the fluoxetine plus folic acid group reported symptoms possibly or probably related to medication, whereas in the fluoxetine plus placebo group 19 (29.7%) patients reported such symptoms (P<0.05). LIMITATIONS AND CONCLUSIONS: Folic acid is a simple method of greatly improving the antidepressant action of fluoxetine and probably other antidepressants. Folic acid should be given in doses sufficient to decrease plasma homocysteine. Men require a higher dose of folic acid to achieve this than women, but more work is required to ascertain the optimum dose of folic acid.

 J Neurol Neurosurg Psychiatry 2000 Aug;69(2):228-32

Homocysteine, folate, methylation, and monoamine metabolism in depression. Bottiglieri T, Laundy M, Crellin R, Toone BK, Carney MW, Reynolds EH.

Department of Neurology, King's College Hospital, London, UK.

OBJECTIVES: Previous studies suggest that folate deficiency may occur in up to one third of patients with severe depression, and that treatment with the vitamin may enhance recovery of the mental state. There are, however, difficulties in interpreting serum and red cell folate assays in some patients, and it has been suggested that total plasma homocysteine is a more sensitive measure of functional folate (and vitamin B12) deficiency. Other studies suggest a link between folate deficiency and impaired metabolism of serotonin, dopamine, and noradrenaline (norepinephrine), which have been implicated in mood disorders. A study of homocysteine, folate, and monoamine metabolism has, therefore, been undertaken in patients with severe depression. METHODS: In 46 inpatients with severe DSM III depression, blood counts, serum and red cell folate, serum vitamin B12, total plasma homocysteine, and, in 28 patients, CSF folate, S-adenosylmethionine, and the monoamine neurotransmitter metabolites 5HIAA, HVA, and MHPG were examined. Two control groups comprised 18 healthy volunteers and 20 patients with neurological disorders, the second group undergoing CSF examination for diagnostic purposes. RESULTS: Twenty four depressed patients (52%) had raised total plasma homocysteine. Depressed patients with raised total plasma homocysteine had significant lowering of serum, red cell, and CSF folate, CSF S-adenosylmethionine and all three CSF monoamine metabolites. Total plasma homocysteine was significantly negatively correlated with red cell folate in depressed patients, but not controls.

CONCLUSIONS: Utilising total plasma homocysteine as a sensitive measure of functional folate deficiency, a biological subgroup of depression with folate deficiency, impaired methylation, and monoamine neurotransmitter metabolism has been identified. Detection of this subgroup, which will not be achieved by routine blood counts, is important in view of the potential benefit of vitamin replacement

Am J Psychiatry 1997 Mar;154(3):426-8

FOLATE, vitamin B12, and homocysteine in major depressive disorder.

Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T.

Depression Clinical and Research Program, Clinical Psychopharmacology Unit, Massachusetts General Hospital, Boston 02114, USA. favam@A1.mgh.harvard.edu

OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment.

VITAMIN B 12:

Am J Psychiatry 2000 May;157(5):715-21

Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study.

Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP.

Epidemiology, Demography, and Biometry Program, National Institute on Aging, Bethesda, MD 20892-9205, USA.

OBJECTIVE: It has been hypothesized that adequate concentrations of vitamin B(12) and folate are essential to maintain the integrity of the neurological systems involved in mood regulation, but epidemiologic evidence for such a link in the general population is unavailable. This study examined whether community-dwelling older women with metabolically significant vitamin B(12) or folate deficiency are particularly prone to depression. METHOD: Serum levels of vitamin B(12), folate, methylmalonic acid, and total homocysteine were assayed in 700 disabled, nondemented women aged 65 years and over living in the community. Depressive symptoms were measured by means of the Geriatric Depression Scale and categorized as no depression, mild depression, and severe depression. RESULTS: Serum homocysteine levels, serum folate levels, and the prevalences of folate deficiency and anemia were not associated with depression status. The depressed subjects, especially those with severe depression, had a significantly higher serum methylmalonic acid level and a nonsignificantly lower serum vitamin B(12) level than the nondepressed subjects. Metabolically significant vitamin B(12) deficiency was present in 14.9% of the 478 nondepressed subjects, 17. 0% of the 100 mildly depressed subjects, and 27.0% of the 122 severely depressed women. After adjustment for sociodemographic characteristics and health status, the subjects with vitamin B(12) deficiency were 2.05 times as likely to be severely depressed as were nondeficient subjects. CONCLUSIONS: In community-dwelling older women, metabolically significant vitamin B(12)deficiency is associated with a twofold risk of severe depression.

Gen Hosp Psychiatry 2002 Mar-Apr;24(2):106-9

Mood disorder with mixed features due to vitamin B(12) and folate deficiency.

Fafouti M, Paparrigopoulos T, Liappas J, Mantouvalos V, Typaldou R, Christodoulou G.

Dept. of Psychiatry, Athens University Medical School, Athens, Greece.

Vitamin B(12) and folate deficiency is often associated with affective disorders mainly of the depressive type. We report a case of a 42-year-old woman with a mood disorder with mixed depressed/manic features that was due to vitamin B(12) and folate deficiency. The psychopathology developed over a five-year period without hematologic or other overt clinical characteristics of pernicious anemia. Replacement treatment with vitamin B(12) and folate was rapidly followed by full clinical remission, electroencephalographic normalization and neuropsychological improvement. At a one-year follow-up this condition was stable. Consequently, patients who respond poorly to psychopharmacologic treatment and/or present with atypical mood symptoms would warrant determination of vitamin B(12) and folate serum levels.

THYROID:

Most psychiatrists now accept that thyroid is a useful augmentation treatment for difficult depression—even if thyroid blood tests are normal. The data is stronger for T3 (cytomel) and for Armour thyroid (pork, 40% T3) than it is for synthroid (T4).

Consider screening for free T3 , free T4, reverse T3, or, with proper precaution and informed consent, empirically try low dose treatment (assuming no contraindications).

1: Int J Neuropsychopharmacol 2000 Jun;3(2):143-147

Thyroid hormone treatment of primary unipolar depression: a review. Joffe RT, Sokolov ST.

A substantial number of depressed patients will fail to respond to standard antidepressant therapy. Thyroid hormones, particularly T3, may be particularly useful in enhancing response to antidepressants. This review focuses on the use of T3 augmentation in unipolar major depression. The study clearly suggests that approximately half of patients will respond to T3 augmentation of antidepressants. There are several limitations to the literature including the fact that most studies have used T3 in tricyclic rather than SSRI failure and most are of relatively short duration, up to 3 wk. Further studies are required of T3 efficacy with newer classes of antidepressants, optimal dose of T3 to be used and the duration of T3 augmentation, particularly if the acute trial is successful.

J Affect Disord 2002 Apr;68(2-3):285-94

Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders. Bauer M, Baur H, Berghofer A, Strohle A, Hellweg R, Muller-Oerlinghausen B, Baumgartner A.

Department of Psychiatry, Klinikum Benjamin Franklin, Freie Universitat Berlin, Berlin, Germany. mjbauer@mednet.ucla.edu

BACKGROUND: Thyroxine (T(4)) in supraphysiological doses has been found to be an effective supplemental treatment in open studies for refractory mood disorders. Unexpectedly, only minimal side effects have been reported. The goal of the present study was to investigate whether healthy controls and depressed patients differ in their ability to tolerate supraphysiological doses of T(4). METHODS: This was an 8-week open study to investigate side effects and levels of thyroid hormones in 13 healthy controls and to compare results with those of 13 patients with refractory depression (unipolar and bipolar) undergoing the similar procedures and T(4) dosing regimen in a previous augmentation study. RESULTS: The rate of discontinuation due to side effects was significantly higher in the control group than for the patients (38% versus 0%). The severity of the side effects in the controls increased significantly during treatment with T(4). The side effect scores of the patients were higher than those of the controls prior to T(4) treatment, but did not change significantly during the treatment period. Although the serum concentrations of thyroid hormones rose significantly in both groups, concentrations of fT(3) and fT(4) were significantly higher in the controls. CONCLUSIONS: Healthy controls and depressed patients respond significantly differently to supraphysiological T(4). Healthy controls experience higher elevations of thyroid hormones in response to supraphysiological T(4), thus inducing significantly more side effects and discontinuation. LIMITATIONS: Open-label study; groups were studied at different times; in contrast to healthy controls, depressed patients were also taking antidepressants. CLINICAL RELEVANCE: Studies provide safety and tolerability data on treatment with supraphysiological doses of T(4).

MELATONIN:

Not much data but some suggestion that melatonin might sometimes help mood, as well as helping sleep. Note: tryptophan becomes 5 Hydroxy tryptophan, which becomes Serotonin, which becomes melatonin.

Exp Gerontol 2001 Feb;36(2):297-310

Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study.

 Am J Psychiatry 1999 May;156(5):710-5

THYROID (AGAIN)

Low levels of transthyretin in the CSF of depressed patients.

Sullivan GM, Hatterer JA, Herbert J, Chen X, Roose SP, Attia E, Mann JJ, Marangell LB, Goetz RR, Gorman JM.

Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.

OBJECTIVE: Transthyretin plays an important role in the transport and distribution of thyroid hormone in the central nervous system (CNS). This study replicated and extended to patients with nonrefractory depressive illness a pilot study indicating that patients with refractory major depression have significantly lower levels of CSF transthyretin than do healthy comparison subjects. METHOD: Lumbar punctures were performed in drug-free subjects with DSM-III-R major depression (N = 18), DSM-III-R bipolar disorder, depressed phase (N = 1), and healthy comparison subjects (N = 24). CSF concentrations of transthyretin, determined by a quantitative dot-immunobinding assay, of the depressed patients and comparison subjects were compared by analysis of covariance (ANCOVA). The relationship between CSF transthyretin levels and Hamilton Depression Rating Scale scores was determined in a subset of the depressed patients. RESULTS: CSF concentrations of transthyretin were significantly lower in the depressed patients than in the comparison subjects by ANCOVA. Within the depressed group there was no significant overall correlation between CSF transthyretin levels and Hamilton depression scale scores, but there was a significant inverse correlation in male depressed patients (N = 8) between CSF transthyretin concentrations and Hamilton depression scores. CONCLUSIONS: Lower CSF transthyretin concentrations in depressed patients may reflect either a stable trait in this population or a state change secondary to depression or other factors. Lower CSF transthyretin concentrations may result in altered CNS thyroid hormone homeostasis. Such alteration could account for certain mood and neurovegetative symptoms of depression and might contribute to failure of standard antidepressant treatment.

MELATONIN:

Bellipanni G, Bianchi P, Pierpaoli W, Bulian D, Ilyia E.

Menopause Center, Madonna delle Grazie Health Institute, Velletri, Rome, Italy.

In aging humans, night levels of melatonin (MEL) decline progressively. Also thyroid and gonadal functions decline during aging while gonadotropins (luteotropic hormone (LH) and follicle stimulating hormone (FSH)) steadily increase. A desynchronization of pineal circadian cyclicity as expressed by the progressive decrease of the MEL night peak may be permissively linked to the onset and progression of menopause. We studied the effects of exogenous, evening administration of MEL on the level of hormones which are known to be involved in the genesis and progression of menopause. Perimenopausal and menopausal women from 42 to 62years of age with no pathology or medication were selected. MEL was measured in saliva to divide them into low, medium and high-MEL patients. Half of them took 3mg MEL and half of them Placebo at bedtime (10-12p.m.) in a fully randomized and double-blind fashion. Three and six months later blood was taken for determination of pituitary (LH, FSH), ovarian, and thyroid hormones I(T3 and T4). All women taking MEL with low basal level of MEL and/or Placebo for three and six months showed a significant increase in levels of thyroid hormones. Before initiation of the study, a negative correlation was found in all women between LH, FSH and basal MEL levels. Within six months of treatment, MEL produced a significant diminution of LH in the younger women (43 to 49year-old), while no effect was seen in the older women (50-62years old). A decrement of FSH was observed in MEL-treated women with low basal MEL levels. In addition, most MEL-treated women reported a general improvement of mood and a significant mitigation of depression. MEL decline during aging may thus signal the derangement of pineal and pituitary-controlled ovarian cyclicity and the progressive quenching of fertility in women. These findings seem to show a recovery of pituitary and thyroid functions in MEL-treated women, towards a more juvenile pattern of regulation.

DHEA:

Several fairly decent studies suggest that DHEA is beneficial in depression. Note DHEA has both estrogenic and androgenic effects. Hence need for informed consent.

Acne, hair growth (androgenic) are most frequent side-effects. Breast cancer from estrogen is greatest theoretical fear (although no data so far to bear that out.)

 Cochrane Database Syst Rev 2000;(2):CD000304

 Dehydroepiandrosterone (DHEA) supplementation for cognition and well-being. Huppert FA, Van Niekerk JK, Herbert J.

Department of Psychiatry, Cambridge University, Box 189 Addenbrooke's Hospital, Cambridge, UK, CB2 2QQ. fah2@cus.cam.ac.uk

BACKGROUND: In view of the theoretical rationale for beneficial effects of DHEA and DHEAS in aging and dementia, we believe it is timely to undertake a thorough investigation of well-conducted studies in this area. This will provide a basis for confirmation of any effect of DHEA/S administration in humans, in large-scale and properly controlled trials, which would evaluate effective dosage, acceptable route and duration of administration and side effect profiles. This is especially pertinent at this time as DHEA is currently being sold in large quantities in health food stores, particularly in the USA. In some cases the recommended dose is different for men and women (50mg/day for men and 25mg/day for women) and the basis for this recommendation needs to be explored.

 OBJECTIVES: To establish whether administration of DHEA, or its sulphate, DHEAS, improves psychological well-being and/or improves cognitive function or reduces the rate of decline of cognitive function in older adults or in individuals with dementia. SEARCH STRATEGY: All available electronic databases, hand searched journals, personal communications and conference abstracts were searched for randomised controlled trials of DHEA in well-being and cognition. The total yield from searching was 415 and the detailed breakdown is given in the body of this review. SELECTION CRITERIA: All relevant randomised controlled trials of DHEA or DHEAS were considered for inclusion in the review. Studies where groups are matched, rather than randomised, were also considered. DATA COLLECTION AND ANALYSIS: Data for the specified outcomes were independently extracted by two reviewers (FAH & JvN) and cross-checked. Any discrepancies were discussed and resolved. Where possible and appropriate, data were pooled and the mean differences estimated.

MAIN RESULTS: The published DHEA trials fall into 2 categories: 1. four German studies in which DHEA was administered for a period of two weeks or less; 2. a USA study in which DHEA was administered for three months. Well-being was assessed in both sets of studies and a significant improvement was reported in the longer duration USA study, while no effect was reported in the shorter duration studies. The USA study used an open-ended questionnaire for self-assessment of well-being and stated that 67% of men and 82% of women reported enhanced well-being on DHEA compared with placebo. There was no significant change on an analogue measure of libido. The German studies assessed mood and well-being with a number of standardised scales and reported no significant effects of DHEA on any of them. Only the German studies examined performance on cognitive tests, i.e. memory, verbal fluency, speed of processing, etc. They reported no significant benefit of DHEA. REVIEWER'S

CONCLUSIONS: The data at present offer limited support for improvement in a sense of well-being following DHEA treatment. This effect was reported only in the longer-term study which used a crude measure of well-being. The data offer no support at present for an improvement in memory or other aspects of cognitive function following DHEA treatment, although cognitive function was only measured in the short-duration trials. In view of the growing public enthusiasm for DHEA supplementation, particularly in the USA, it is clear that high-quality trials need to be undertaken in older adults, in which (a) the duration of DHEA treatment is in excess of two weeks, (b) the number of participants is large enough to detect effects if they exist, and (c) the outcome measures include validated scales for assessment of mood and well-being, and objective tests of cognitive function. Recently, studies of DHEA supplementation in clinical depression and Alzheimer's Disease have been completed in the USA. As soon as the results are available these studies will be reviewed. Currently, two trials (in France and the USA) in normal elderly are in progress.

1: N Engl J Med 1999 Sep 30;341(14):1013-20

Dehydroepiandrosterone replacement in women with adrenal insufficiency. Arlt W, Callies F, van Vlijmen JC, Koehler I, Reincke M, Bidlingmaier M, Huebler D, Oettel M, Ernst M, Schulte HM, Allolio B.

Department of Endocrinology, Medical University Hospital, Wuerzburg, Germany. w.arlt@medizin.uni-wuerzburg.de

BACKGROUND: The physiologic role of dehydroepiandrosterone in humans is still unclear. Adrenal insufficiency leads to a deficiency of dehydroepiandrosterone; we therefore, investigated the effects of dehydroepiandrosterone replacement, in patients with adrenal insufficiency. METHODS: In a double-blind study, 24 women with adrenal insufficiency received in random order 50 mg of dehydroepiandrosterone orally each morning for four months and placebo daily for four months, with a one-month washout period. We measured serum steroid hormones, insulin-like growth factor I, lipids, and sex hormone-binding globulin, and we evaluated well-being and sexuality with the use of validated psychological questionnaires and visual-analogue scales, respectively. The women were assessed before treatment, after one and four months of treatment with dehydroepiandrosterone, after one and four months of placebo, and one month after the end of the second treatment period. RESULTS: Treatment with dehydroepiandrosterone raised the initially low serum concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione, and testosterone into the normal range; serum concentrations of sex hormone-binding globulin, total cholesterol, and high-density lipoprotein cholesterol decreased significantly. Dehydroepiandrosterone significantly improved overall well-being as well as scores for depression and anxiety. For the global severity index, the mean (+/-SD) change from base line was -0.18+/-0.29 after four months of dehydroepiandrosterone therapy, as compared with 0.03+/-0.29 after four months of placebo (P=0.02). As compared with placebo, dehydroepiandrosterone significantly increased the frequency of sexual thoughts (P=0.006), sexual interest (P=0.002), and satisfaction with both mental and physical aspects of sexuality (P=0.009 and P=0.02, respectively). CONCLUSIONS: Dehydroepiandrosterone improves well-being and sexuality in women with adrenal insufficiency.

1: Biol Psychiatry 1999 Jun 15;45(12):1533-41

Comment in:

· Biol Psychiatry. 1999 Jun 15;45(12):1531-2.

Dehydroepiandrosterone treatment of midlife dysthymia.

Bloch M, Schmidt PJ, Danaceau MA, Adams LF, Rubinow DR.

Behavioral Endocrinology Branch, National Institute of Mental Health, Bethesda, MD 20892-1276, USA.

BACKGROUND: This study evaluated the efficacy of the adrenal androgen, dehydroepiandrosterone, in the treatment of midlife-onset dysthymia. METHODS: A double-blind, randomized crossover treatment study was performed as follows: 3 weeks on 90 mg dehydroepiandrosterone, 3 weeks on 450 mg dehydroepiandrosterone, and 6 weeks on placebo. Outcome measures consisted of the following. Cross-sectional self-ratings included the Beck Depression Inventory, and visual analogue symptom scales. Cross-sectional objective ratings included the Hamilton Depression Rating Scale, the Cornell Dysthymia Scale and a cognitive test battery. Seventeen men and women aged 45 to 63 years with midlife-onset dysthymia participated in this study. Response to dehydroepiandrosterone or placebo was defined as a 50% reduction from baseline in either the Hamilton Depression Rating Scale or the Beck Depression Inventory. RESULTS: In 15 patients who completed the study, a robust effect of dehydroepiandrosterone on mood was observed compared with placebo. Sixty percent of the patients responded to dehydroepiandrosterone at the end of the 6-week treatment period compared with 20% on placebo. A significant response was seen after 3 weeks of treatment on 90 mg per day. The symptoms that improved most significantly were anhedonia, loss of energy, lack of motivation, emotional "numbness," sadness, inability to cope, and worry. Dehydroepiandrosterone showed no specific effects on cognitive function or sleep disturbance, although a type II error could not be ruled out. CONCLUSIONS: This pilot study suggests that dehydroepiandrosterone is an effective treatment for midlife-onset dysthymia.

ESTROGEN

Perimenopausal women who are depression often do very well with estrogen. Post-menopausal women who are depressed, usually do not do well with estrogen.

1: Expert Opin Pharmacother 2001 Apr;2(4):527-35

Sex hormones and their impact on dementia and depression: a clinical perspective. Almeida OP, Barclay L.

UWA Department of Psychiatry, Level 6 - Ainslie House, Royal Perth Hospital, GPO Box X2213, Perth, WA 6847, Australia. osvalm@cyllene.uwa.edu.au

Sex hormones have often been associated with changes in behavioural and mental abilities. This paper reviews the scientific literature published between 1990 and 2000 investigating the effects of oestrogen, testosterone and dehydroepiandrosterone (DHEA) on depression and dementia. Oestrogen seems to have a positive effect in preventing, but not treating, Alzheimer's disease. Oestrogen use may also improve mood amongst women with postnatal or perimenopausal depression; however, it may contribute to increasing depressive symptoms in women with premenstrual dysphoria. The behavioural effects of testosterone and DHEA remain unclear but the results of preliminary reports suggest that their use is associated with improved mood. At present, there is not enough hard data to support the use of sex hormones and DHEA for the treatment of depression or memory deficits.

TESTOSTERONE:

Men with low testsosterone might do better with replacement. Studies are attractive but not conclusive. Obviously follow PSA and prostate exam. Women with low teststosterone might also improve with T. Again, the studies aren’t great.

J Geriatr Psychiatry Neurol 2000 Summer;13(2):93-101

The male menopause and mood: testosterone decline and depression in the aging male--is there a link?

Margolese HC.

Department of Psychiatry, McGill University, Montreal, Quebec.

The objective of this study was to review the literature on the hormonal changes that occur in aging males in order to determine if testosterone declines in relation to depressed mood and if testosterone might prove useful in treatment of depression. Pertinent articles were identified through a MEDLINE search from 1966 to 1999 and by careful review of the bibliographies of articles most relevant to the topic. There is a moderate decline of total testosterone and more significant decline of bioavailable testosterone in aging males. Elderly males who are depressed appear to have the lowest testosterone levels. In eugonadal males, testosterone replacement does not have a significant effect on mood; in hypogonadal males, some studies show an effect whereas others do not. In several small studies of depressed hypogonadal males, testosterone was effective in alleviating depression. Major side effects of testosterone include increased hematocrit and potential effects on the prostate and lipid metabolism. Testosterone replacement as primary or adjuvant treatment of depression may prove useful in elderly, hypogonadal males who fail to respond to conventional antidepressants. Further studies are needed to confirm these initial impressions.

Arq Neuropsiquiatr 1999 Sep;57(3A):701-6

Sex playing with the mind. Effects of oestrogen and testosterone on mood and cognition.

Almeida OP.

University of Western Australia (UWA), Department of Psychiatry and Behavioural Science, Perth, Australia. osvalm@cyllene.uwa.edu.au

Women now spend more than 1/3 of their lives in a state of oestrogen deprivation as a result of increased life expectancy. A similar, but milder, hypogonadal state has been described for elderly men. This paper aims to review the available literature on the effects of both oestrogen and testosterone on mood and cognition. Oestrogen replacement therapy of postmenopausal women is associated with improvements in measures of well being and decline in depression scores. In addition, oestrogen seems to augment the response of postmenopausal women with major depression to antidepressant treatment. Most studies designed to investigate the impact of oestrogen on cognition indicate that replacement therapy is associated with better performance on neuropsychological tests, particularly in measures of verbal memory and fluency. The data also supports claims that oestrogen replacement therapy reduces the risk of Alzheimer's disease in later life and improves response of patients to anticholinesterase treatment. Data on the effects of testosterone is sparser. Preliminary findings suggest that testosterone therapy may improve mood when used in isolation or in association with oestrogen. The effects of testosterone on cognitive functioning are less clear--some studies indicate that the administration of testosterone to non-demented subjects is associated with better visuospatial functioning and deterioration of verbal skills. In summary, gonadal hormones seem to modulate various aspects of mental functioning. If future studies prove this to be true, hormone replacement therapy should have a major impact on the physical and mental health of older people in the years to come.

INOSITOL:

There are quite a few well designed but small studies suggesting benefit from very high dose Inositol for anxiety, depression, OCD. They are published in good journals. However, all are from the same Israeli group. No one else seems interested.

Psychopharmacol Bull 1995;31(1):167-75

Inositol treatment in psychiatry.

Benjamin J, Agam G, Levine J, Bersudsky Y, Kofman O, Belmaker RH.

Division of Psychiatry, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Inositol, a naturally occurring isomer of glucose, is a key intermediate of the phosphatidyl-inositol (PI) cycle, a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. The suggestion that lithium might treat mania via its reduction of inositol levels led to experiments showing that pharmacological doses of peripheral inositol reverse behavioral effects of lithium in animals and side effects of lithium in man. Cerebrospinal fluid (CSF) levels of inositol are low in depression. An open-label, add-on trial of inositol in depression suggested a beneficial effect. In a subsequent 1-month, parallel-groups, double-blind, placebo-controlled study of 28 patients, inositol was effective as sole therapy for depression (p = .043). Inositol was also effective for panic disorder in a double-blind, random-assignment, placebo-controlled crossover study of 21 patients, with 4 weeks in each phase (p = .02); the effect was comparable to that of imipramine in recent studies.

: J Clin Psychopharmacol 2001 Jun;21(3):335-9

Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder.

Palatnik A, Frolov K, Fux M, Benjamin J.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beer-Sheba, Israel.

Only 70% of patients respond to current treatments for panic disorder, and many discontinue drugs because of side effects. myo-Inositol, a natural isomer of glucose and a precursor for the second-messenger phosphatidyl-inositol system, has previously been found superior to placebo in the treatment of depression, panic disorder, and obsessive-compulsive disorder (OCD), but a direct comparison with an established drug has never been performed. A double-blind, controlled, random-order crossover study was undertaken to compare the effect of inositol with that of fluvoxamine in panic disorder. Twenty patients completed 1 month of inositol up to 18 g/day and 1 month of fluvoxamine up to 150 mg/day. Improvements on Hamilton Rating Scale for Anxiety scores, agoraphobia scores, and Clinical Global Impressions Scale scores were similar for both treatments. In the first month, inositol reduced the number of panic attacks per week (mean and SD) by 4.0 (2) compared with a reduction of 2.4 (2) with fluvoxamine (p = 0.049). Nausea and tiredness were more common with fluvoxamine (p = 0.02 and p = 0.01, respectively). Because inositol is a natural compound with few known side effects, it is attractive to patients who are ambivalent about taking psychiatric medication. Continuing reports of inositol's efficacy in the treatment of depression, panic disorder, and OCD should stimulate replication studies.

MAGNESIUM:

Many nutritionally oriented docs are convinced that magnesium is sub par in the

US population. Main risk is cardiac, but low magnesium increases vulnerability to anxiety, migraine, etc. However, anxiety, pain, etc, increases magnesium loss in urine. Hence a vicious cycle. Few good studies, but an attractive theory and little to lose. Note: measuring serum mg is usually not worth it; magnesium status requires more complex measures.

Am J Cardiol 1997 Mar 15;79(6):768-72

Comment in: Am J Cardiol. 1997 Oct 1;80(7):976.

Clinical symptoms of mitral valve prolapse are related to hypomagnesemia and attenuated by magnesium supplementation.

Lichodziejewska B, Klos J, Rezler J, Grudzka K, Dluzniewska M, Budaj A, Ceremuzynski L.

Department of Cardiology, Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.

Mitral valve prolapse syndrome (MVP) is a frequent disorder characterized by a number of complaints which lessen the quality of life. The pathogenesis of MVP symptoms has not been fully elucidated. Hyperadrenergic activity and magnesium deficiency have been suggested. This study was designed to verify the concept that heavily symptomatic MVP is accompanied by hypomagnesemia and to elucidate whether magnesium supplementation alleviates the symptoms and influences adrenergic activity. We assessed serum magnesium in 141 subjects with heavily symptomatic primary MVP and in 40 healthy controls. Decreased serum magnesium was found in 60% of patients and in 5% of controls (p <0.0001). Patients with low serum magnesium were subjected to magnesium or placebo supplementation in a double-blind, crossover fashion. Typical symptoms of MVP (n = 13), intensity of anxiety, and daily excretion of catecholamines were determined. After 5 weeks, the mean number of symptoms per patient decreased from 10.4 +/- 2.1 to 5.6 +/- 2.5 (p <0.0001), and a significant reduction in weakness, chest pain, dyspnea, palpitations, and anxiety was observed. Increased noradrenaline excretion before and after magnesium was seen in 63% and 17% of patients, respectively (p <0.01). Mean daily excretion of noradrenaline and adrenaline was significantly diminished after magnesium. It is concluded that many patients with heavily symptomatic MVP have low serum magnesium, and supplementation of this ion leads to improvement in most symptoms along with a decrease in catecholamine excretion.

B-Vitamins:

1: Psychopharmacology (Berl) 1997 Jan;129(1):66-71

Thiamine supplementation mood and cognitive functioning.

Benton D, Griffiths R, Haller J.

Department of Psychology, University of Wales Swansea, UK.

One hundred and twenty young adult females took either a placebo or 50 mg thiamine, each day for 2 months. Before and after taking the tablets, mood, memory and reaction times were monitored. An improvement in thiamine status was associated with reports of being more clearheaded, composed and energetic. The taking of thiamine had no influence on memory but reaction times were faster following supplementation. These influences took place in subjects whose thiamine status, according to the traditional criterion, was adequate.

 Multivitamins

Psychopharmacology (Berl) 2000 Jun;150(2):220-5

The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind placebo-controlled trial.

Carroll D, Ring C, Suter M, Willemsen G.

School of Sport and Exercise Sciences, University of Birmingham, UK. carrolld@bham.ac.uk

RATIONALE: Vitamin and mineral supplements may be associated with improved psychological status. OBJECTIVE: The present study tested the effects of a multivitamin and mineral supplement (Berocca) on psychological well-being. METHODS: In a double-blind randomised-control trial, 80 healthy male volunteers were assigned to either Berocca or placebo. Questionnaires measuring psychological state were completed and a blood sample taken to determine plasma zinc concentration on day 1 (pre-treatment) and again on day 28 (post-treatment), following 28 days of treatments, which were administered at a dosage of one tablet daily. At the end of the study, the acceptability of the treatment and participants' awareness of treatment condition were assessed, as was habitual dietary behaviour. RESULTS: Relative to placebo, treatment with Berocca was associated with consistent and statistically significant reductions in anxiety and perceived stress. Participants in the Berocca group also tended to rate themselves as less tired and better able to concentrate following treatment. In addition, participants registered more somatic symptoms following placebo than following Berocca. These effects cannot be attributed to differences in the acceptability of the two treatments or to participants guessing what treatment they received. CONCLUSION: These findings demonstrate that Berocca significantly reduces anxiety and perceived stress.

GLUTEN:

About 2% of Americans have anti gliadin antibodies, the significance of which is not clear. Most don’t have diarrhea, but if depression coexists, I favor a three month trial of gluten free. The migraine study below showed that one HLA type accounted for an impressive series of refractory migraineurs who improved with gluten elimination. Whether diarrhea or blunted villi occur may not be relevant.

Am J Gastroenterol 1999 Mar;94(3):839-43

Depression in adult untreated celiac subjects: diagnosis by the pediatrician.

Corvaglia L, Catamo R, Pepe G, Lazzari R, Corvaglia E.

Department of Pediatric Gastroenterology, St. Orsola Hospital, University of Bologna, Italy.

Untreated celiac disease can lead to serious behavioral disorders. We describe three adult patients with undiagnosed or untreated celiac disease without particular intestinal signs, causing persistent depressive symptoms in three of the parents of our pediatric patients. In two of the three cases, the pediatrician suspected the diagnosis when taking the family history of the children. In fact, a diagnosis of celiac disease was made during childhood, when they had intestinal symptoms, but the gluten-free diet was spontaneously interrupted during the teenage period because of the disappearance of the typical intestinal signs. In the third case the mother was tested for antiendomysium antibodies (EmA), as she had a diagnosed celiac child. In all three patients, the depressive symptoms improved quickly with a gluten-free diet. In conclusion, celiac disease should be taken into consideration in the presence of behavioral and depressive disorders, particularly if they are not responsive to the usual antidepressive therapy.

Dig Dis Sci 2001 Jul;46(7):1500-5

High prevalence of celiac disease in Italian general population.

Volta U, Bellentani S, Bianchi FB, Brandi G, De Franceschi L, Miglioli L, Granito A, Balli F, Tiribelli C.

Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Policlinico S. Orsola-Malpighi, Universita di Bologna, Italy.

The worldwide increase of celiac disease prompted us to assess its prevalence in the Italian general population. The 3483 inhabitants of Campogalliano were tested for immunoglobulin A anti-endomysial antibodies. Twenty subjects showed antibody positivity and duodenal biopsy detected typical mucosal lesions of celiac disease in 17 of them; the remaining three cases had a normal villous architecture, but the finding of increased gamma/delta intraepithelial lymphocytes in all and the heterodimer DQA1*0501, DQB1*0201 in two of them was consistent with potential celiac disease. Only one patient had an overt malabsorption syndrome, characterized by diarrhea, weight loss, and severe weakness. In eight subjects atypical symptoms of celiac disease, such as dyspepsia and depression, were present, whereas the remaining subjects were silent. Celiac disease was more frequent in younger age groups. Our cross-sectional design study demonstrates that celiac disease prevalence in the Italian general population is 4.9 per 1000 (95% CI 2.8-7.8), increasing up to 5.7 per 1000 (95% CI 3.5-8.8) with the inclusion of potential cases.

: Neurology 2001 Feb 13;56(3):385-8

Headache and CNS white matter abnormalities associated with gluten sensitivity.

Hadjivassiliou M, Grunewald RA, Lawden M, Davies-Jones GA, Powell T, Smith CM.

Department of Clinical Neurology, The Royal Hallamshire Hospital, Sheffield, UK. m.hadjivassiliou@sheffield.ac.uk

The authors describe 10 patients with gluten sensitivity and abnormal MRI. All experienced episodic headache, six had unsteadiness, and four had gait ataxia. MRI abnormalities varied from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Symptomatic response to gluten-free diet was seen in nine patients.

CARNITINE

Bipolar Disord 2002 Feb;4(1):61-6

Acetyl Carnitine is probably effective in Alzheimer’s. It’s certainly effective for peripheral vascular disease. Possibly also for depression and fatigue.

31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam K, McClure RJ.

Neurophysics Laboratory, Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA. pettegre@pitt.edu

OBJECTIVE: This 12-week study of two elderly, depressed subjects investigated the effect of acetyl-L-carnitine (ALCAR) treatment on the Hamilton Depression Rating Scale (HDRS) and on measures of high-energy phosphate and membrane phospholipid metabolism. METHODS: Two mildly depressed (HDRS 15-20), non-demented male subjects 70 and 80 years old were compared with six non-demented controls (all males, mean age of 73.6 +/- 3.6 years). High-energy and membrane phospholipid metabolites were measured by phosphorus magnetic resonance spectroscopic imaging (31P MRSI) analysis. HDRS and 31P MRSI measurements were taken at entry, 6 and 12 weeks for the depressed subjects. RESULTS: 31P MRSI analysis revealed elevated levels of phosphomonesters [PME(s - tau(c))] in the prefrontal region of these mildly depressed subjects, which decreased with ALCAR treatment and showed a trend for correlation of the PME(s - tau(c)) levels with HDRS. ALCAR treatment also resulted in increasing levels of the prefrontal phosphocreatine (PCr), which correlated with HDRS. CONCLUSIONS: In the prefrontal region, the mildly depressed subjects compared with controls had elevated PME(s - tau(c)) levels which normalized after 12 weeks of ALCAR and increased PCr levels after ALCAR treatment. These preliminary findings suggest further studies are warranted.

 Drugs Exp Clin Res 1987;13(7):417-23

L-acetylcarnitine in depressed elderly subjects. A cross-over study vs placebo.

Tempesta E, Casella L, Pirrongelli C, Janiri L, Calvani M, Ancona L.

Department of Psychiatry and Psychology, Catholic University of the Sacred Heart, Rome, Italy.

An open, cross-over study was performed on a population of 24 geriatric patients hospitalized because of depressive syndrome. They were subdivided, according to Hamilton's Scale as modified for the aged, into low- and high-score subgroups. The study period covered 2 months. Half the patients received acetylcarnitine for 1 month and placebo thereafter (Group A); the other half received placebo and acetyl-carnitine thereafter (Group B). Statistical evaluation was twofold: parametrical analysis of variance was carried out on 4 subgroups (A1, A2, B1 and B2) and analysis of the score percentage modifications before and after treatment was performed on Groups A and B. The experimental results showed that acetylcarnitine treatment was highly effective and statistically significant in subgroups A1/B1, A2/B2, A1, B1 and B2. In particular, it should be noted that depressive tendencies were significantly modified in most groups, whereas general somatic symptoms as well as anxiety, asthenia and sleep disturbances proved to be little affected. Clinical evaluation, carried out by calculation of modifications in pre- and post-treatment score percentages, provided clear evidence that acetylcarnitine was particularly effective in patients showing more serious clinical symptoms. The drug caused no side-effects at the doses and regimens used.

: J Clin Endocrinol Metab 2001 Aug;86(8):3579-94

Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial.

Benvenga S, Ruggeri RM, Russo A, Lapa D, Campenni A, Trimarchi F.

Cattedra & Sezione di Endocrinologia, Dipartimento Clinico-sperimentale di Medicina e Farmacologia, University of Messina School of Medicine, 98125 Messina, Italy. s.benvenga@me.nettuno.it

Old studies in animals and unblinded studies in a few hyperthyroid patients suggested that L -carnitine is a periferal antagonist of thyroid hormone action at least in some tissues. This conclusion was substantiated by our recent observation that carnitine inhibits thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts. In the randomized, double-blind, placebo-controlled 6-month trial reported here, we assessed whether 2 or 4 g/d oral L-carnitine were able to both reverse and prevent/minimize nine hyperthyroidism- related symptoms. We also evaluated changes on nine thyroid hormone-sensitive biochemical parameters and on vertebral and hip mineral density (bone mineral density). Fifty women under a fixed TSH-suppressive dose of L -T(4) for all 6 months were randomly allocated to five groups of 10 subjects each. Group 0 associated placebo for 6 months; groups A2 and A4 started associating placebo (first bimester), substituted placebo with 2 or 4 g/d carnitine (second bimester), and then returned to the association with placebo. Groups B2 and B4 started associating 2 and 4 g/d carnitine for the first two bimesters, and then substituted carnitine with placebo (third bimester). Symptoms and biochemical parameters worsened in group 0. In group A, symptoms and biochemical parameters worsened during the first bimester, returned to baseline or increased minimally during the second bimester (except osteocalcin and urinary OH-proline), and worsened again in the third bimester. In group B, symptoms and biochemical parameters (except osteocalcin and urinary OH-proline) did not worsen or even improved over the first 4 months; they tended to worsen in the third bimester. In both the A and B groups, the two doses of carnitine were similarly effective. At the end of the trial, bone mineral density tended to increase in groups B and A (B > A). In conclusion, L-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a beneficial effect on bone mineralization. Because hyperthyroidism depletes the body deposits of carnitine and since carnitine has no toxicity, teratogenicity, contraindications and interactions with drugs, carnitine can be of clinical use.

FISH OIL

We need more studies but it’s clear that depressed and anxious people tend to have low omega 3’s in rbcs—which several labs can measure. Several small double blind studies suggest benefit for the depressive phase of bipolar disorder.

The proper dose is not clear. Also not clear whether EPA or DHA is more important.

Arch Gen Psychiatry 1999 May;56(5):407-12

Comment in:

· Arch Gen Psychiatry. 1999 May;56(5):413-4; discussion 415-6.

· Arch Gen Psychiatry. 2000 Jul;57(7):715.

· Arch Gen Psychiatry. 2000 Jul;57(7):716-7.

· Arch Gen Psychiatry. 2001 May;58(5):512-3.

Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial.

Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB.

Brigham and Women's Hospital, Department of Psychiatry, Harvard Medical School, Boston, Mass, USA. alstoll@mclean.harvard.edu

BACKGROUND: Omega3 fatty acids may inhibit neuronal signal transduction pathways in a manner similar to that of lithium carbonate and valproate, 2 effective treatments for bipolar disorder. The present study was performed to examine whether omega3 fatty acids also exhibit mood-stabilizing properties in bipolar disorder. METHODS: A 4-month, double-blind, placebo-controlled study, comparing omega3 fatty acids (9.6 g/d) vs placebo (olive oil), in addition to usual treatment, in 30 patients with bipolar disorder. RESULTS: A Kaplan-Meier survival analysis of the cohort found that the omega3 fatty acid patient group had a significantly longer period of remission than the placebo group (P = .002; Mantel-Cox). In addition, for nearly every other outcome measure, the omega3 fatty acid group performed better than the placebo group. CONCLUSION: Omega3 fatty acids were well tolerated and improved the short-term course of illness in this preliminary study of patients with bipolar disorder.

: Psychiatr Clin North Am 2000 Dec;23(4):785-94

Docosahexanoic acid and omega-3 fatty acids in depression.

Mischoulon D, Fava M.

Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Geographic areas where consumption of DHA is high are associated with decreased rates of depression. DHA deficiency states, such as alcoholism and the postpartum period, also are linked with depression. Individuals with major depression have marked depletions in omega-3 FAs (especially DHA) in erythrocyte phospholipids compared with controls. These data suggest that DHA may be associated with depression, and the limited data available on supplementation with DHA or other omega-3 FAs seem to support the hypothesis that DHA may have psychotropic effects. Overall, the use of EFAs is promising, particularly in view of the many illnesses potentially treatable with these substances; however, larger, carefully designed studies are needed to establish whether DHA is an effective and safe antidepressant, mood stabilizer, or antipsychotic. A few preliminary trials of DHA are in progress, but no studies comparing DHA against placebo or against an established antidepressant have been carried out. Studies to address this issue are being developed at the Massachusetts General Hospital. Studies likely will require escalating doses of DHA, eventually reaching high levels so as to ensure that patients will avoid a potentially ineffective subclinical dose. Careful monitoring of dietary intake among subjects also will necessary because a high intake of omega-3-rich foods may confound results. Finally, large-scale, placebo-controlled, double-blind trials comparing the efficacy and safety of DHA against standard antidepressants are required before psychiatrists can recommend DHA therapy as effective and safe for the treatment of depression and other mood disorders. Given the popularity of self-medication by patients who already are taking marketed antidepressants, studies examining the use of DHA as an augmentor to standard antidepressants may answer whether DHA can occupy a niche as an augmenting agent for patients who have made a partial response or have not responded to conventional antidepressants. Considering that natural medications generally seem best for treating mild to moderate illness, the role of DHA as a therapy for minor and subsyndromal depression also should be considered. It is hoped that studies of these types will help to clarify some of the knowledge gaps outlined in this article.

J Affect Disord 1998 Mar;48(2-3):149-55

Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients.

Edwards R, Peet M, Shay J, Horrobin D.

University Department of Psychiatry, University of Sheffield, UK.

BACKGROUND: There is a hypothesis that lack of n-3 polyunsaturated fatty acids (PUFAs) is of aetiological importance in depression. Docosahexaenoic acid, a member of the n-3 PUFA family, is a crucial component of synaptic cell membranes. The aim of this study was to measure RBC membrane fatty acids in a group of depressed patients relative to a well matched healthy control group. METHOD: Red blood cell (RBC) membrane levels, and dietary PUFA intake were measured in 10 depressed patients and 14 matched healthy control subjects. RESULTS: There was a significant depletion of RBC membrane n-3 PUFAs in the depressed subjects which was not due to reduced calorie intake. Severity of depression correlated negatively with RBC membrane levels and with dietary intake of n-3 PUFAs. CONCLUSION: Lower RBC membrane n-3 PUFAs are associated with the severity of depression. LIMITATIONS: Although patient numbers were small, confounding factors were well controlled for and the results were highly significant. Results of the dietary data would tend to be weakened due to the limitations associated with dietary assessment. CLINICAL RELEVANCE: The findings raise the possibility that depressive symptoms may be alleviated by n-3 PUFA supplementation.

 Am J Psychiatry 2002 Sep;159(9):1596-8

Randomized, placebo-controlled study of ethyl-eicosapentaenoic acid as supplemental treatment in schizophrenia.

Emsley R, Myburgh C, Oosthuizen P, van Rensburg SJ.

Department of Psychiatry, University of Stellenbosch, Tygerberg, Cape Town, South Africa. rae@sun.ac.za

OBJECTIVE: The study investigated the efficacy and tolerability of ethyl-eicosapentaenoic acid (E-EPA) as add-on treatment in chronic, severe schizophrenia. METHOD: A randomized, parallel-group, double-blind, placebo-controlled, fixed-dose, add-on study was conducted over 12 weeks. Forty patients with persistent symptoms after at least 6 months of stable antipsychotic treatment received E-EPA or placebo, in addition to their existing treatment. RESULTS: At 12 weeks, the E-EPA group had significantly greater reduction of Positive and Negative Syndrome Scale total scores and of dyskinesia scores than the placebo group. CONCLUSIONS: EPA may be an effective and well-tolerated add-on treatment in schizophrenia.

Nutr Neurosci 2002 Feb;5(1):37-41

The effect of docosahexaenoic acid on aggression in elderly Thai subjects--a placebo-controlled double-blind study.

Hamazak T, Thienprasert A, Kheovichai K, Samuhaseneetoo S, Nagasawa T, Watanabe S.

Department of Clinical Application, Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, Japan. hamazaki@ms.toyama-mpu.ac.jp

Docosahexaenoic acid (DHA) administration controls extraggression (aggression against others) in young subjects under psychological stress. However, it is not known whether its administration affects extraggression of elderly subjects. Forty Thai subjects of 50-60 years of age (22 males and 18 females) were recruited from Silpakorn University and nearby villages. They were allocated to the control and DHA groups in a double-blind fashion, and took 10 mixed plant oil capsules and 10 DHA capsules (1.5g DHA/day) for 2 months, respectively. Extraggression was measured with a psychological test (PF Study) at the beginning and end of the study. Just prior to the PF Study at the end of the study, subjects were asked to watch a stressful videotape as a stressor component. The average DHA intake from food was 150-160mg/day. In the group of university employees, extraggression did not change over time with placebo, whereas extraggression significantly decreased (31 +/- 13 to 24 +/- 13%, P = 0.04 by the paired-t test, P = 0.04 by ANOVA). In the group of villagers, there was no significant difference between the control and DHA groups in extraggression. The DHA administration favorably controlled extraggression in at least elderly white-collar workers. The daily intake of 150-160 mg/day of DHA was not enough to control extraggression.

: Arch Gen Psychiatry 2002 Oct;59(10):913-9

A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs.

Peet M, Horrobin DF.

Swallownest Court Hospital, Sheffield, England.

BACKGROUND: In depressed patients, low blood levels of eicosapentaenoic acid are seen. We tested the antidepressive effect of ethyl-eicosapentaenoate in these patients. METHODS: We included 70 patients with persistant depression despite ongoing treatment with an adequate dose of a standard antidepressant. Patients were randomized on a double-blind basis to placebo or ethyl-eicosapentaenoate at dosages of 1, 2, or 4 g/d for 12 weeks in addition to unchanged background medication. Patients underwent assessment using the 17-item Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Rating Scale, and the Beck Depression Inventory. RESULTS: Forty-six (88%) of 52 patients receiving ethyl-eicosapentaenoate and 14 (78%) of 18 patients receiving placebo completed the 12-week study with no serious adverse events. The 1-g/d group showed a significantly better outcome than the placebo group on all 3 rating scales. In the intention-to-treat group, 5 (29%) of 17 patients receiving placebo and 9 (53%) of 17 patients receiving 1 g/d of ethyl-eicosapentaenoate achieved a 50% reduction on the Hamilton Depression Rating Scale score. In the per-protocol group, the corresponding figures were 3 (25%) of 12 patients for placebo and 9 (69%) of 13 patients for the 1-g/d group. The 2-g/d group showed little evidence of efficacy, whereas the 4-g/d group showed nonsignificant trends toward improvement. All of the individual items on all 3 rating scales improved with the 1-g/d dosage of ethyl-eicosapentaenoate vs placebo, with strong beneficial effects on items rating depression, anxiety, sleep, lassitude, libido, and suicidality. CONCLUSION: Treatment with ethyl-eicosapentaenoate at a dosage of 1 g/d was effective in treating depression in patients who remained depressed despite adequate standard therapy.

TRYPTOPHAN: 5-hydroxy tryptophan and tryptophan are the precursors of serotonin (and melatonin). About one-third of depressed patients have low ratios of tryptophan to the neutral amino acids (valine, leucine, isoleucine, phenylalanine, tyrosine), which compete with Tryptophan for entry into the brain. Overwhelming evidence shows that reducing tryptophan by feeding a tryptophan free amino acid mix worsens depression. You’d think, therefore, there would be many studies testing the opposite i.e. supplementing with T. Unfortunately, there are not. However, treating with 5htp or 5 OHTP makes sense in my view. Caution on hyperserotonin syndrome if combine T with St. John’s or SSRI (but measuring T level first should drastically reduce risk).

Psychopharmacology (Berl) 2002 Aug;163(1):42-53

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.

Murphy FC, Smith KA, Cowen PJ, Robbins TW, Sahakian BJ.

MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Cambridge CB2 2EF, UK.

RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.

Psychopharmacology (Berl) 2001 May;155(2):123-7

Tryptophan depletion in SSRI-recovered depressed outpatients.

Spillmann MK, Van der Does AJ, Rankin MA, Vuolo RD, Alpert JE, Nierenberg AA, Rosenbaum JF, Hayden D, Schoenfeld D, Fava M.

Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA.

RATIONALE: Recently, a number of studies have challenged the finding that acute tryptophan depletion (TD) increases depressive symptoms in medicated, formerly depressed patients. The present study examined the effects of acute nutritional TD on remitted depressed patients currently treated with selective serotonin reuptake inhibitors. In an attempt to clarify conflicting earlier findings, the effects of a number of clinical variables on outcome were also investigated. METHODS: Ten patients underwent TD in a double-blind, controlled, balanced crossover fashion. The control session followed the procedure of Krahn et al. (1996 Neuropsychopharmacology 15:325-328). Sessions were 5-8 days apart. RESULTS: TD was significantly related to increased scores on clinician-rated depression and anxiety scales, and on self-rated depression, anxiety, and somatic symptoms. The control challenge had no effect, despite the fact that the reductions in plasma tryptophan during the control session were unexpectedly high. Some evidence was found for a threshold in the relationship between reduction of plasma tryptophan and mood response. CONCLUSIONS: The mood effect of TD in medicated, formerly depressed patients was confirmed. A threshold may exist for mood effects following TD, implying that recent negative findings may have been caused by insufficient depletion. No other predicting or mediating factors were identified, although the variable "history of response pattern to medication" deserves further study.

J Psychiatry Neurosci 2000 Sep;25(4):337-46

Preliminary randomized double-blind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder: antidepressant and hypnotic effects.

Levitan RD, Shen JH, Jindal R, Driver HS, Kennedy SH, Shapiro CM.

Clarke Division, Centre for Addiction and Mental Health, Toronto, Ont. robert_levitan@camh.net

OBJECTIVE: Because the initial phase of treatment of depression with a selective serotonin reuptake inhibitor is often complicated by a delayed onset of action of the antidepressant or severe insomnia or both, we investigated whether tryptophan, an amino acid with both antidepressant-augmenting and hypnotic effects, would benefit patients with depression at the beginning of treatment with fluoxetine. DESIGN: Randomized, double-blind, placebo-controlled trial. PATIENTS: Thirty individuals with major depressive disorder. INTERVENTIONS: Treatment over 8 weeks with 20 mg of fluoxetine per day and either tryptophan (2 to 4 g per day) or placebo. OUTCOME MEASURES: Mood was assessed using the 29-item Hamilton Depression Rating Scale (HDRS-29) and the Beck Depression Inventory (BDI). Laboratory sleep studies were done at baseline and after 4 and 8 weeks of treatment using standard procedures. RESULTS: During the first week of treatment, there was a significantly greater decrease in HDRS-29 depression scores, and a similar trend in BDI scores, in the tryptophan/fluoxetine group than in the placebo/fluoxetine group. No significant differences were noted at later time points. With respect to sleep measures, there was a significant group-by-time interaction for slow-wave sleep at week 4. Further analysis revealed a significant decrease in slow-wave sleep after 4 weeks of treatment in the placebo/fluoxetine group, but not in the tryptophan/fluoxetine group. No cases of serotonin syndrome occurred, and the combination was well tolerated, although the 4 g per day dosage of tryptophan produced daytime drowsiness. CONCLUSIONS: Combining 20 mg of fluoxetine with 2 g of tryptophan daily at the outset of treatment for major depressive disorder appears to be a safe protocol that may have both a rapid antidepressant effect and a protective effect on slow-wave sleep. Further large-scale studies are needed to confirm these initial findings.

Biol Psychiatry 2000 Aug 15;48(4):327-9

Tryptophan depletion and risk of depression relapse: a prospective study of tryptophan depletion as a potential predictor of depressive episodes.

Moreno FA, Heninger GR, McGahuey CA, Delgado PL.

Department of Psychiatry, College of Medicine, The University of Arizona Health Sciences Center, Tucson 85724, USA.

BACKGROUND: This study investigated the relationship between depressive symptom response during tryptophan depletion and future depressive episodes. METHODS: Twelve subjects with prior major depressive episodes in remission and medication-free for > or =3 months (patients), and 12 matched healthy (control) subjects received two tryptophan depletion tests 1 week apart. During follow-up the Hamilton Depression Rating Scale was administered weekly for 1 month, monthly for 3 months, and once at 6 and 12 months. RESULTS: With results from both tests, tryptophan depletion has a sensitivity of 78%, specificity of 80%, positive predictive value of 70%, and negative predictive value of 86% to identify future depressive episodes. Survival analysis shows that mood response to tryptophan depletion reliably predicts major depressive episodes during the follow-up year (r =.2725, p =.014). CONCLUSIONS: Tryptophan depletion may be clinically useful in identifying individuals at risk for future major depressive episodes.

Biol Psychiatry 1999 Feb 1;45(3):313-20

A placebo-controlled clinical trial of L-tryptophan in premenstrual dysphoria.Steinberg S, Annable L, Young SN, Liyanage N.

Department of Psychiatry, St. Mary's Hospital, Montreal, Quebec, Canada.

BACKGROUND: Antidepressant drugs, including specific serotonin reuptake inhibitors, have been shown to be beneficial in the treatment of premenstrual dysphoric disorders. The present study tests the efficacy of L-tryptophan, which acts specifically on serotonergic neurons, in this disorder. METHODS: In a randomized controlled clinical trial, 37 patients with premenstrual dysphoric disorder were treated with L-tryptophan 6 g per day, and 34 were given placebo. The treatments were administered under double-blind conditions for 17 days, from the time of ovulation to the third day of menstruation, during three consecutive menstrual cycles. RESULTS: The Visual Analogue Scales (VAS) revealed a significant (p = .004) therapeutic effect of L-tryptophan relative to placebo for the cluster of mood symptoms comprising the items of dysphoria, mood swings, tension, and irritability. The magnitude of the reduction from baseline in maximum luteal phase VAS-mood scores was 34.5% with L-tryptophan compared to 10.4% with placebo. CONCLUSIONS: These results suggest that increasing serotonin synthesis during the late luteal phase of the menstrual cycle has a beneficial effect in patients with premenstrual dysphoric disorder.

: J Affect Disord 1998 Jul;50(1):23-7

Efficacy of light versus tryptophan therapy in seasonal affective disorder.

Ghadirian AM, Murphy BE, Gendron MJ.

Department of Psychiatry, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada.

BACKGROUND: Although light therapy has become the accepted treatment for patients suffering from seasonal affective disorder (SAD, winter depression), almost 40% of these patients do not respond, and require an alternative treatment. METHODS: The therapeutic effects of light versus tryptophan on SAD were studied in a repeated measures design in 13 SAD patients (11 women, 2 men). Light therapy for 2 weeks or tryptophan for 4 weeks was given, separated by a one week washout period. All were assessed with the modified Hamilton Depression Rating scale (SIGH-SAD) at the beginning and end of each treatment. RESULTS: Four (31%) of the patients did not respond to either therapy. Four tryptophan-resistant patients responded to light therapy, while one light therapy-resistant patient responded to tryptophan. Relapse occurred rapidly after stopping light therapy but not after stopping tryptophan therapy. CONCLUSIONS: There were significant therapeutic effects of both light (p = 0.012) and tryptophan (p = 0.014) on SAD, which were not significantly different from each other. There may be a time difference between the residual pharmacokinetic effects after stopping therapy. LIMITATIONS: The groups studied were small. This was an open study. CLINICAL RELEVANCE: Tryptophan was equally effective to light therapy in treating SAD, but relapse after withdrawal of tryptophan probably occurs

Neuropsychobiology 2001;44(3):134-8

Predictive value of amino acids in the treatment of major depression with fluvoxamine.

Mauri MC, Boscati L, Volonteri LS, Scalvini ME, Steinhilber CP, Laini V, Zamberlan F.

Department of Internal Medicine, University of Milan, Clinical Neuropsychopharmacology Unit, IRCCS Ospedale Maggiore di Milano, Milan, Italy. maurimc@polic.cilea.it

Sixteen outpatients (mean age +/- SD 50.18 +/- 11.55 years; 11 females and 5 males) affected by major depression without melancholia (DSM-IV) were included in the study. The control group consisted of 11 healthy volunteers (mean age +/- SD 39.90 +/- 13.39 years; 2 females and 9 males). Patients were treated with fluvoxamine (FVX) 100-300 mg daily. Clinical assessment was performed using the Hamilton Rating Scales for Anxiety and Depression (HRS-A; HRS-D) and the Clinical Global Impression Scale (CGI) at basal time (T(0)), after 4 weeks and after 8 weeks (T(8)). Plasma and platelet amino acid levels were determined at T(0) in all the subjects and also at T(8) in depressed patients. A significant clinical improvement was observed in depressed patients according to the HRS-A (p = 0.004), HRS-D (p = 0.008) and CGI (p = 0.002). A negative correlation (r = -0.53, p = 0.049) was found between platelet levels of valine and HRS-D improvement rate. Patients showed significantly higher tyrosine/large neutral amino acids (LNAAs) and lower tryptophan/LNAAs, ratios which could represent an index of good response to a serotonergic drug like FVX. Copyright 2001 S. Karger AG, Basel