-IBIS-1.7.6-
tx
mental/emotional
depression
Nutrition

dietary guidelines

etiologic factors:
Nutrient deficiencies
Vitamin B6: coenzyme in the production of monoamine neurotransmitter; also cofactor for delta-6-desaturase, the rate limiting enzyme for the production of PGE1, a hormone that may be helpful in prevention of depression (Essential Fatty Acids Immunity and Mental Health, by Charles Bates). B6 is also a vital cofactor for the conversion of tryptophan into serotonin and melatonin.
(Russ. Nutrition Reports International, 1983;867-873; Adams. Lancet, Apr.28, 1973: 897-904; Baumblatt, et al. Lancet, April 18, 1970, 832-833.)
EGOT TEST (Tahoma Labs) Erythrocyte glutamic oxaloacetic transaminase activation. Start with 100 mg three times daily. Measure the activity of this enzyme. Double the dose to 200 mg three times daily and, after 10 days, measure the enzyme activity again. If it goes up, double the dose again and see if the activity of the enzyme goes up again. Continue doubling until enzyme activity plateaus. Obviously, symptoms should be monitored as well. The dose does not need to go higher once the patient responds favorably.
Folate: often deficient in psychiatric patients
Vitamin B12
Iron
Thiamin
Vitamin C
Essential fatty acids (especially omega-6 fatty acids)
Excessive consumption of methylxanthines such as theobromine, theophylin or caffeine from coffee, black tea, cola or chocolate
Excessive consumption of simple sugars triggering hypoglycemic reactions.
Imbalance in brain nucleotides
Drug-induced: Oral Contraceptives. It is thought that in a significant number of cases, depression is caused by oral contraceptives. which create a vitamin B6 deficiency. Other nutrient deficiencies thought to be caused by oral contraceptives are folate, vitamin B1, vitamin C, and vitamin B2. Other drugs which can cause depression include alcohol, nicotine, cannabis, caffeine, corticosteroids, betablockers, and other anti-hypertensive medications.
Hypothyroidism is one of the most frequent causes of depression and must be ruled out.

eating principles:
Consider food sensitivities
Hypoglycemic diet
Treat hypothyroidism: Low thyroid function is a very common cause of depression and should always be considered.
Chelate heavy metals
Avoid toxic fumes including cigarette smoke. Inhaling toxic fumes results in an increased level of cortisol and may exacerbate a pre-existing hypoglycemia. Cortisol decreases the uptake of tryptophan in the brain resulting in decreased levels of serotonin.
• Elimination/rotation diet, rotation diet, rotation diet expanded

therapeutic foods:
• Foods high in omega-3 fatty acids: nut, seed, vegetable oils (safflower, canola, walnut, sunflower, flax seed), evening primrose oil, black currant oil
• Foods rich in Vitamin B6
• Foods high in tryptophan: nuts, eggs, meat, fish, dairy
• If supplementing tryptophan: give with cofactors (Vitamins B3, B6, and C) and whole wheat toast, bananas, walnuts, pineapples that are high in serotonin

specific foods
» for Stagnant Liver Qi or Stagnancy in the Liver channel:
• Foods that invigorate the Qi, Liver foods, sour foods, Dispersing foods, foods that open channels
• Citrus peel, figs, honey
• Liver-cleansing foods: beets, carrots, artichokes, lemons, parsnips, dandelion greens, watercress, burdock root

fresh juices:
• Carrot (Walker, 145.)
• Carrot and spinach (Walker, 145.)
• Carrot, beet, and cucumber (Walker, 145.)
• Lemon juice in warm water

specific remedies:
• Tea from licorice, Chinese black dates, and wheat chaff (the part that floats on the surface of water) (Ni, 147.)

Therapeutic considerations:
Exercise is essential is the treatment of depression.
Negative Ions
Full spectrum lighting and bright lights

avoid:
Hypoglycemia
Avoid foods containing tyramine if the patient is on MAO inhibitors. Cheese, chicken, liver, sardines, red wine, yeast, beer, soured cream, eggplant, and green bean pods should all be avoided.
Avoid Aspartame which increases CNS tyrosine and phenylalanine while decreasing tryptophan availability. This results in decreased levels of serotonin in the brain.
Consider food sensitivities, avoid food intolerances
(Gettis A. Nutr Health 1989;6:135-146; King DS. Biol Psychiatr 1981;16:3-19; Brown M, et al. Practitioner 1981;225:1651-1654; Rippere V. Nutr Health 1984;3(3):125-136.)
• Meat, alcohol, hot sauces, spicy foods, fried foods, fatty foods, rich foods, salty foods
Coffee, caffeine (Greden JF, et al. Am J Psychiatry 1978;135:963-966; Gilliland K, Bullock W. Adv Alcohol Subst Abuse 1983-84;3:53-73; Christensen L. J Applied Nutr 1988;40:44-50.)
Sugar, diet high in simple carbohydrates, especially if indications of hypoglycemia. (Christensen L. J Applied Nutr 1988;40:44-50.)
Avoid toxic fumes including cigarette smoke. Inhaling toxic fumes results in an increased level of cortisol. (Marz R. 453, 1997.)

supplements

Vitamin B6: 50-100 mg three times daily; is a cofactor for the conversion of tryptophan into serotonin and niacin; especially indicated when PMS is also present or associated with aggravation of depressive symptoms.; further indicated when birth control pills are being used.
(Adams. Lancet, Apr.28: 897-904, 1973; Baumblatt, et al. Lancet, April 18, 1970, .832-833; Russ CS, et al. Nutr Rep Internat 1983;27:867-873; Gunn ADG. Int J Vitam Nutr Res 1985;(Suppl 27):213-224; Kleijnen J, et al. Brit J Obstet Gynaecol 1990;97:847-852.); see also below regarding phenelzine and oral contraceptive interactions
Note: There are times when B6 supplementation can make symptoms worse. One explanation is that some cases of depression are due to an imbalance of the brain amines rather than a deficiency. B6 might accentuate an amine that is already out of balance. The other explanation is that some people may have an enzyme that is extremely sensitive to B6 and might convert the tryptophan outside the blood brain barrier (BBB) into metabolites that cant cross the blood-brain barrier. (Marz, 454, 1997)
Vitamin B12: IM 1000 mcg once per week; vitamin B12 deficiency can contribute to depression in the absence of anemia
(Lindenbaum J, et al. N Engl J Med 1988;318:1720-1728; Holmes JM. J Nutr Med 1991;2:89-90; Ellis FR, Nasser S. Br J Nutr 1973;30:277-283. Marz, 454, 1997)
• Vitamin C 3 g per day.
Folate: 3-5 mg per day. Check for hypersegmented neutrophils and also serum folate.
(Godfry, PSA, et al. Lancet, 336:392-95, 1990; Reynolds E, et al. Br J Psychiatr 1970;117:287-292; Coppen A, et al. J Affective Disorders 1986;10:9-113; Di Palma C, et al. Curr Ther Res 1994;55:559-567; Carney MWP, 1979.)
• Zinc
Omega-3 oils, particularly DHA, also EPA: play key roles in healthy functioning of the nervous system. DHA levels are usually lower in individuals diagnosed with depression; likewise, low EPA levels have been associated with greater severity of depression.
(Adams PB, et al. Lipids 1996;31:S157-S161; Edwards R, et al. J Affect Disord 1998;48:149-155.)
DHEA (dehydroepiandrosterone): Several clinical trials, including one double blind study using 90 mg per day for six weeks, have found significant improvements in major depression.
(Wolkowitz OM, et al. Biol Psychiatr 1997;41:311-318; Wolkowitz OW, et al. Am J Psychiatry 1999;156:646-649.)
DL-phenylalanine: Start with 500 mg per day and work up to 3-4 g per day. This is a precursor for epinephrine and phenylethylamine (PEA). PEA has amphetamine-like stimulant properties. Chocolate contains high levels of PEA.
(Beckman H, et al. J Neural Transmission 1977;41:123-134; Beckmann H, et al. Arch Psychiatr Nervenkr 1979;227:49-58; Sabelli HC, et al. J Clin Psychiatr 1986;47:66-70.)
S-Adenosyl-L-Methionine (SAMe): acts as methyl group donor in numerous reactions in the brain. It affects the turnover rate of monoamines such as serotonin and dopamine.
(Salmaggi P, et al. Psychother Psychosom 1993;59(1):34-40; Bell KM, et al. Acta Neurol Scand 1994;154(suppl):15-18; Kagan BL, et al. Am J Psychiatr 1990;147:591-595; Fava M, et al. Acta Psychiatr Scand 1992;86:42-45; Bressa GM. Acta Neurol Scand 1994;154(suppl):7-14.)
Phosphatidylserine: plays a key role in neurotransmitter levels related to mood. In one study, a group of older women taking 300 mg demonstrated significantly lower levels of depression than did those on placebo.
(Maggioni M, et al. Acta Psychiatr Scand 1990;81:265-270.)
Tryptophan (substrate): 3-6 g per day; give together with pyridoxine; take on empty stomach with juice. Stimulates the production of serotonin and melatonin, both of which have been found to useful for depression. If the patient has insomnia along with depression, then tryptophan seems to be even more effective. Studies generally show mixed results. There may be specific depressed people who respond very well to treatment with tryptophan.
(D’Elia G, et al. Acta Psychiatr Scand 1978;57:239-252. Chouinard. Adv Biol Psychiat. 10:47-66,1983; van Praag HM, Lemus C, 1986; 49-88.)
Note: Be careful when giving tryptophan. If the patient is deficient in B6, then he/she may convert tryptophan into metabolic by-products that can inhibit the transport of tryptophan into the brain. In fact it is possible to cause a net deficiency in the brain. (Marz, 454, 1997)
Generally contraindicated for patients taking MAO Inhibitors.
5-HTP (5-hydroxytryptophan): feeds serotonin synthesis pathway; showing promise in most cliinical trials. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. Generally contraindicated for patients taking MAO Inhibitors.
(Angst J, et al. Arch Psychiatr Nervenkr 1977;224:175-186; D’Elia G, et al Acta Psychiatr Scand 1978;57:239-252; Van Praag H, de Hann S. Psychiatry Res 1980;3:75-83; Nolen WA, et al. Br J Psychiatry 1985;147:16-22; Nolen WA, et al. Acta Psychiatr Scand 1988;78:676-683; Birmaher B, Kaufman J, Brent DA, Dahl RE, Perel JM, al-Shabbout M, Nelson B, Stull S, Rao U, Waterman GS, et al. Arch Gen Psychiatry. 1997 Dec;54(12):1113-9.; Birdsall TC. Altern Med Rev. 1998 Aug;3(4):271-280.)
Tyrosine: 2 g three times daily. Precursor for norepinephrine and thyroid hormones; depression is often associated with lower levels of tyrosine, as is oral contraceptive use.
(Rose DP, Cramp DG. Clin Chem Acta 1970;29:49-53; Kishimoto H, Hama Y. Yokohama Med Bull 1976;27:89-97; Moller SE. Lancet 1979;ii:472; Gelenberg AJ, et al. Am J Psychiatr 1980;137:622-623; Gibson, Gelenberg. Adv Biol Psychiat. 1983;10:148-59; Buist. Int Clin Nutr. Rev. 1983;3:1; van Praag HM. Psychopharm Bull. 20(3):599-602, 1984.)
Inositol: individuals suffering from depression may have lower levels but clinical efficacy of supplementation has not been demonstrated
NADH: positive outcomes in treating chronic fatigue, proposed value in treatment of depression
Evening Primrose Oil: It has been found that depressed people in general have lower levels of PGE1. Usually they have a decreased activity of delta 6 desaturase and their ability to make more PGE1 is compromised. This is especially true of people whose ancestry is 25% or higher of Celtic Irish, Welsh, Scottish, Scandinavian or Native Indian origin. See Essential Fatty Acids and Immunuity in Mental Health by Charles Bates. (Marz, 455, 1997)
• Consider methionine, threonine, thyroid protomorphogens (Marz)

» drug interactions:
MAO inhibitors, esp. phenelzine (Nardil), and vitamin B6: phenelzine depletes vitamin B6; may require supplementation (Heller, Friedman, 1983; 75: 887-888.)
MAO inhibitors, esp. phenelzine (Nardil), and tyramine: gastrointestinal MAO is essential for adequate breakdown of tyramine (Sullivan, Shulman, 1984; 29: 707-711.)
tricyclic antidepressants [amitriptyline (Elavil), imipramine (Tofranil)]: cause increased appetite (Stein, et al, 1985; 33: 687)
• Vitamin B6 and oral contraceptives: Vitamin B6 deficiency may develop as oral contraptives require Vitamin B6 to facilitate tryptophan to niacinamide; resulting deficiency may lead to depression (Goodhart, Shils, 6th ed., 450.)


footnotes

Adams PB, Lawson S, Sanigorski A, Sinclair AJ. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996 Mar;31 Suppl:S157-161.
Abstract: In this study of 20 moderately to severely depressed patients, diagnosed using current research diagnostic criteria and excluding known bipolar affective disorder and reactive depression, we investigated relationships between severity of depression and levels and ratios of n-3 and n-6 long-chain polyunsaturated fatty acids (PUFA) in plasma and erythrocyte phospholipids (PL). Severity of depression was measured using the 21-item Hamilton depression rating scale (HRS) and a second linear rating scale (LRS) of severity of depressive symptoms that omitted anxiety symptoms. There was a significant correlation between the ratio of erythrocyte PL arachidonic acid (AA) to eicosapentaenoic acid (EPA) and severity of depression as rated by the HRS (P < 0.05) and the LRS for depression (P < 0.01). There was also a significant negative correlation between erythrocyte EPA and the LRS (P < 0.05). The AA/EPA ratio in plasma PL and the ratio of erythrocyte long-chain (C20 and C22 carbon) n-6 to long-chain n-3 PUFA were also significantly correlated with the LRS (P < 0.05). These findings do not appear to be simply explained by differences in dietary intake of EPA. We cannot determine whether the high ratios of AA/EPA in both plasma and erythrocyte PL are the result of depression or whether tissue PUFA change predate the depressive symptoms. We suggest, however, that our findings provide a basis for studying the effect of the nutritional supplementation of depressed subjects, aimed at reducing the AA/EPA ratio in tissues and severity of depression.

Adams PW, Wynn V, Rose DP, et al. Effect of pyridoxine hydrochloride (Vitamin B6) upon depression associated with oral contraception. Lancet 1973;I:897-904.
Abstract: 22 depressed women were suspected of having B6 deficiency depression due to BCP. 1/2 of them took a placebo for 2 months and the other 1/2 20mg B6 2x/day. They then switched. 11 of the women were found to have decreased serum B12 levels in the blood. Every one of these women responded favorably when on the B6 while none of the women who were not deficient responded.

Angst J, Woggon B, Schoepf J. The treatment of depression with L-5-hydroxytryptophan versus imipramine. Results of two open and one double-blind study. Arch Psychiatr Nervenkr 1977;224:175-186.

Barkai AI, Dunner DL, Gross HA, et al. Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder. Biol Psych 1978;13:65-72.

Baumblatt, Michael, and Winston. B6 and the Pill. Lancet, April 18, 1970, 832-833.
Abstract: 58 women who were depressed and taking the pill were treated with 25mg B6 2x/day at first sign of depression PMS. After 3 months of therapy more than 75% of the women reported either complete relief or considerable improvement in their symptoms. The 44 women who seemed to respond to B6 were then asked to discontinue treatment to see if symptoms would return. All the women refused!!

Beckman H, Strauss MA, Ludolph E. DL-Phenylalanine in depressed patients: an open study. J Neural Transmission 1977;41:123-134.

Beckmann H, Athen D, Olteanu M, Zimmer R. DL-phenylalanine versus imipramine: a double-blind controlled study. Arch Psychiatr Nervenkr 1979;227:49-58.
Abstract: 20 Patients received 75-200mg of DL-phenylalanine. After 3 weeks, 8 patients had complete recovery, 4 had a good response, 4 experienced a mild-moderate response, and 4 had no response.

Bell IR, Markley EJ, King DS, Asher S, Marby D, Kayne H, Greenwald M, Ogar DA, Margen S. Polysymptomatic syndromes and autonomic reactivity to nonfood stressors in individuals with self-reported adverse food reactions. J Am Coll Nutr. 1993 Jun;12(3):227-38.

Bell KM, Potkin SG, Carreon D, Plon L. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand 1994;154(suppl):15-18.
Abstract: INTRODUCTION--The relationship between plasma levels of S-adenosylmethionine (SAMe), an endogenous methyl donor, and clinical response were studied in patients with a DSM-III-R diagnosis of major depression. MATERIAL AND METHODS--A double-blind randomized protocol comparing oral SAMe with oral desipramine, involving a total of 26 patients, was employed. RESULTS--At the end of the 4-week trial, 62% of the patients treated with SAMe and 50% of the patients treated with desipramine had significantly improved. Regardless of the type of treatment, patients with a 50% decrease in their Hamilton Depression Scale (HAM-D) score showed a significant increase in plasma SAMe concentration. CONCLUSION--The significant correlation between plasma SAMe levels and the degree of clinical improvement in depressed patients regardless of the type of treatment suggests that SAMe may play an important role in regulating mood.

Birdsall TC. 5-Hydroxytryptophan: a clinically-effective serotonin precursor. Altern Med Rev. 1998 Aug;3(4):271-280. (Review)
Abstract: 5-Hydroxytryptophan (5-HTP) is the intermediate metabolite of the essential amino acid L-tryptophan (LT) in the biosynthesis of serotonin. Intestinal absorption of 5-HTP does not require the presence of a transport molecule, and is not affected by the presence of other amino acids; therefore it may be taken with meals without reducing its effectiveness. Unlike LT, 5-HTP cannot be shunted into niacin or protein production. Therapeutic use of 5-HTP bypasses the conversion of LT into 5-HTP by the enzyme tryptophan hydroxylase, which is the rate-limiting step in the synthesis of serotonin. 5-HTP is well absorbed from an oral dose, with about 70 percent ending up in the bloodstream. It easily crosses the blood-brain barrier and effectively increases central nervous system (CNS) synthesis of serotonin. In the CNS, serotonin levels have been implicated in the regulation of sleep, depression, anxiety, aggression, appetite, temperature, sexual behaviour, and pain sensation. Therapeutic administration of 5-HTP has been shown to be effective in treating a wide variety of conditions, including depression, fibromyalgia, binge eating associated with obesity, chronic headaches, and insomnia.

Birkmayer JGD, Birkmayer W. The coenzyme nicotinamide adenine dinucleotide (NADH) as biological antidepressive agent: Experience with 205 patients. New Trends Clin Neuropharmacol 1991;5:19-25.

Birmaher B, Kaufman J, Brent DA, Dahl RE, Perel JM, al-Shabbout M, Nelson B, Stull S, Rao U, Waterman GS, Williamson DE, Ryan ND. Neuroendocrine response to 5-hydroxy-L-tryptophan in prepubertal children at high risk of major depressive disorder. Arch Gen Psychiatry. 1997 Dec;54(12):1113-1119.
Abstract: BACKGROUND: Altered serotonergic function has been observed in prepubertal children and adults with an acute episode of major depressive disorder (MDD). However, it is not known whether these alterations are present prior to the onset of MDD. METHODS: A serotonergic precursor, 5-hydroxy-L-tryptophan (L-5HTP) (oxitriptan) (0.8 mg/kg), was administered through an indwelling catheter to 36 children at high risk of MDD (with high family loading for MDD), 31 children with MDD, and 23 low-risk normal controls (with low family loading for mood disorders and no history of psychopathology). Blood samples for cortisol, prolactin (PRL), and growth hormone were obtained every 15 minutes for 180 minutes, beginning 30 minutes before L-5HTP infusion. RESULTS: Children at high risk of MDD and children with MDD had similar hormonal responses following L-5HTP infusion. After controlling for baseline values, both groups secreted significantly less cortisol and more PRL than did the low-risk normal controls, with the PRL finding being limited to girls. There were no between-group differences in baseline cortisol, PRL, or growth hormone secretion measures. CONCLUSIONS: Before the onset of affective illness, high-risk children had the same pattern of neuroendocrine response to the L-5HTP challenge as did children with MDD. These results extend earlier findings of altered serotonergic regulation in association with early-onset depression and indicate that these alterations may represent a trait marker for depression in children.

Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: Meta-analysis of clinical studies. Acta Neurol Scand 1994;154(suppl):7-14.
Abstract: INTRODUCTION--S-adenosyl-l-methionine (SAMe) is a naturally-occurring substance which is a major source of methyl groups in the brain. MATERIAL AND METHODS--We conducted a meta-analysis of the studies on SAMe to assess the efficacy of this compound in the treatment of depression compared with placebo and standard tricyclic antidepressants. RESULTS--Our meta-analysis showed a greater response rate with SAMe when compared with placebo, with a global effect size ranging from 17% to 38% depending on the definition of response, and an antidepressant effect comparable with that of standard tricyclic antidepressants. CONCLUSION--The efficacy of SAMe in treating depressive syndromes and disorders is superior with that of placebo and comparable to that of standard tricyclic antidepressants. Since SAMe is a naturally occurring compound with relatively few side-effects, it is a potentially important treatment for depression.

Brown M, Gibney M, Husband PR, Radcliffe M. Food allergy in polysymptomatic patients. Practitioner 1981 Nov;225(1361):1651-1654.

Buist. The therapeutic predictability of tryptophan and tyrosine in the treatment of depression. Int Clin Nutr Rev. 1983;3:1.
Abstract: 2 groups of depressed patients were studied. Group A, which had low urinary levels of the norepinephrine metabolite, MHPG, failed to respond to amitryptyline (Elavil), which tends to raise norepinephrine levels more than serotonin. Rather they responded to imiprimine (tofranil), which tends to raise the level of serotonin. Group B, which had high levels of MHPG, responded more to amitryptylin (Elavil) which tends to raise levels of norepinephrine. They tended to not respond to tofranil.

Carney MWP. Psychiatric aspects of folate deficiency. Folic Acid, in Neurology, Psychiatry and Internal Medicine. Botez, Reynolds, eds., New York: Raven Press, 1979.
Abstract: 13 of 36 patients with endogenous depression or schizophrenia were found to have low serum folate levels. They were treated with folic acid along with standard treatment. 12 of the 13 subjects treated with the folate made a full social recovery (either with or without residual symptoms vs. 16/23 controls. Of 18 patients with endogenous depression who were hospitalized 10 or more days, the 10 folate treated patients average 23.3 days while the 8 controls averaged 32.9 days, a significant difference.

Chouinard G, Young SN, Annable L, Sourkes TL. Tryptophan dosage critical for its antidepressant effect. Br Med J. 1978 May 27;1(6124):1422.

Chouinard G. Tryptophan in the treatment of depression and mania. Adv Biol Psychiat. 1983;10:47-66..
Abstract: 8 studies on the action of tryptophan in patients who were unipolar or of uncertain polarity were reviewed. 5 of the studies showed improvement of the majority of the patients, but they all lacked controls.

Christensen L, Somers S. Comparison of nutrient intake among depressed and nondepressed individuals. Int J Eat Disord. 1996 Jul;20(1):105-109.
Abstract: OBJECTIVE: The study investigated the nutrient intake of depressed and nondepressed subjects. METHOD: Twenty-nine depressed subjects and a matched group of nondepressed subjects completed a 3-day food record. RESULTS: Results revealed that depressed and nondepressed groups consume similar amounts of all nutrients except protein and carbohydrates. Nondepressed subjects consume more protein and depressed subjects consume more carbohydrates. The increase in carbohydrate consumption comes primarily from an increase in sucrose consumption. DISCUSSION: The increased carbohydrate consumption is consistent with the carbohydrate cravings characteristic of the depressed and may relate to the development or maintenance of depression.

Christensen L, Bourgeois A, Cockroft R. Dietary alteration of somatic symptoms and regional brain electrical activity. Biol Psychiatry. 1991 Apr 1;29(7):679-682.

Christensen L. Psychological distress and diet-effects of sucrose and caffeine. J Applied Nutr 1988;40:44-50.

Coppen A, Chaudrhy S, Swade C. Folic acid enhances lithium prophylaxis. J Affective Disorders 1986;10:9-113.
Abstract: 42 pts. with affective disorders on lithium therapy received either 200mcg folate or placebo. Treatment lasted for 1 year and results showed a small insignificant change in the affective morbidity index (AMI) in the folate group compared to the placebo. In the unipolar patients that received the folate a significant improvement was noted in their average Beck depression scores. Overall it was noted that there was a correlation to the degree of depression and what the level of folate was in the tissues as measured by RBC measurements.

D’Elia G, Hanson L, Raotma H. L-tryptophan and 5-hydroxytryptophan in the treatment of depression. A review. Acta Psychiatr Scand 1978;57:239-252. (Review)

De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res 1992;52:478-485.

Di Palma C, Urani R, Agricola R, et al. Is methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment. Curr Ther Res 1994;55:559-567.

Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disord 1998 Mar;48(2-3):149-155.
Abstract: 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.

Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness. Br J Nutr. 1973;30:277-283.

Fava M, Rosenbaum JF, MacLaughlin R, Falk WE, Pollack MH, Cohen LS, Jones L, Pill L. Neuroendocrine effects of S-adenosyl-L-methionine, a novel putative antidepressant. J Psychiatr Res. 1990;24(2):177-184.

Fava M, Rosenbaum JF, Birnbaum R, Kelly K, Otto MW, MacLaughlin R. The thyrotropin-releasing hormone as a predictor of response to treatment in depressed outpatients. Acta Psychiatr Scand 1992 Jul;86(1):42-45.
Abstract: We evaluated the predictive value of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in 32 depressed outpatients completing a double-blind placebo-controlled trial of s-adenosyl-l-methionine (SAMe), which failed to show any significant difference between SAMe and placebo. Treatment response was defined as the change in Hamilton Rating Scale for Depression (HRSD-24) score between baseline and the end of the six-week trial. Subjects with TSH response outside the normal range (7-25 uU/ml) had a significantly greater response than patients with a normal response. There was also a significant correlation between absolute deviations from the mean TSH response (16 uU/ml) and changes in HRSD-24 scores.

Gelenberg AJ, Wojcik JD, Growdon JH, et al. Tyrosine for the treatment of depression. Am J Psychiatr 1980 May;137(5):622-623.

Gettis A. Food sensitivities and psychological disturbance: a review. Nutr Health 1989;6(3):135-146. (Review)
Abstract: The literature dealing with the relationship between food sensitivities and psychological disturbance is reviewed. Numerous theorists and researchers believe the problems of persons presenting with adverse reactions to foods are psychological when immunological techniques fail to confirm an allergic basis. However, there is mounting evidence that adverse reactions to foods can most likely be caused by a variety of mechanisms, and that food sensitivities may indeed cause or exacerbate symptoms of a psychological nature.

Gibson, Gelenberg. Tyrosine for the treatment of depression. Adv Biol Psychiat. 1983;10: 148-59.
Abstract: 3/5 patients had at least a 50% reduction of symptoms compared to 1/4 on the placebo. The reduction in depression was positively correlated with the increases in fasting plasma tyrosine.

Gilliland K, Bullock W. Caffeine: a potential drug of abuse. Adv Alcohol Subst Abuse 1983-84 Fall-Winter;3(1-2):53-73. (Review)

Godfry, PSA, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet, 336:392-95, 1990.
Abstract: 24/76 pts with major depression referred as out patients or candidates for psychiatric hospitalization had borderline or definite folate deficiency according to red-cell folate levels. These 24 people who were low in folate and were proven to have normal B12 levels, randomly received placebo or 15mg folate in addition to standard psychotropic drugs. After 3 and 6 months there were significant improvements noted in the folate supplemented group compared to the placebo group.

Greden JF, Fontaine P, Lubetsky M, Chamberlin K. Anxiety and depression associated with caffeinism among psychiatric inpatients. Am J Psychiatry 1978 Aug;135(8):963-966.
Abstract: Among 83 hospitalized adult psychiatric patients, 22% reported being high caffeine consumers (750 mg or more per day); these patients scored significantly greater on the State-Trait Anxiety Index and the Beck Depression Scale than moderate and low consumers. High consumers described significantly more clinical symptoms, felt that their physical health was not as good, and reported greater use of sedative-hypnotics and minor tranquilizers. Since caffeine modifies catecholamine levels, inhibits phosphodiesterase breakdown of cyclic AMP, and sensitizes receptor sites, association of caffeinism with both anxiety and depressive symptoms is possible.

Gunn ADG. Vitamin B6 and the premenstrual syndrome (PMS). Int J Vitam Nutr Res 1985;(Suppl 27):213-224. (Review)

Holmes JM. Cerebral manifestations of vitamin B12 deficiency. J Nutr Med. 1991;2:89-90.

Kagan BL, Sultzer DL, Rosenlicht N, et al. Oral S-adenosyl-methionine in depression: A randomized, double-blind, placebo-controlled trial. Am J Psychiatr 1990;147:591-595.

Kawachi I, Willett WC, Colditz GA, Stampfer MJ, Speizer FE. A prospective study of coffee drinking and suicide in women. Arch Intern Med 1996;156:521-525.

King DS. Can allergic exposure provoke psychological symptoms? A double-blind test. Biol Psychiatry. 1981 Jan;16(1):3-19.
Abstract: 30 patients with depression, confusion, difficulty concentrating or other psychological symptoms noted significantly grater cognitive emotional symptoms when tested with sub-lingual antigens (foods and chemicals) compared to placebos (p=0.0001). There was also found to be the most severe reactions to the real antigens than compared to the placebo. There was also a greater variability of heart rate change was found for allergens than for placebos (p=0.008).

King DS. Psychological and behavioral effects of food and chemical exposure in sensitive individuals. Nutr Health. 1984;3(3):137-151. (Review)

Kishimoto H, Hama Y. The level and diurnal rhythm of plasma tryptophan and tyrosine in manic-depressive patients. Yokohama Med Bull 1976;27:89-97.

Kleijnen J, Riet GT, Knipschild P. Vitamin B6 in the treatment of the premenstrual syndrome. A review. Brit J Obstet Gynaecol 1990;97:847-852.

Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728.

Maggioni M, Picotti GB, Bondiolotti GP, Panerai A, Cenacchi T, Nobile P, Brambilla F. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand 1990 Mar;81(3):265-270.
Abstract: The effects of phosphatidylserine (BC-PS) on cognitive, affective and behavioural symptoms were studied in a group of 10 elderly women with depressive disorders. Patients were treated with placebo for 15 days, followed by BC-PS (300 mg/day) for 30 days. The Hamilton Rating Scale for Depression, Gottfries-Brane-Steen Rating Scale, Nurse's Observation Scale for Inpatient Evaluation and Buschke Selective Reminding Test were administered before and after placebo and after BC-PS therapy, to monitor changes in depression, memory and general behaviour. At the same time, basal plasma levels of noradrenaline, MHPG, DOPAC, HVA and 5-HIAA, and GH/beta-endorphin/beta-lipotropin responses to clonidine stimulation were measured. BC-PS induced consistent improvement of depressive symptoms, memory and behaviour. No changes in amine metabolite levels or in hormonal responses to alpha 2-adrenoceptor stimulation were observed.

Martinsen EW, Medhus A, Sandivik L. Effects of aerobic exercise on depression: a controlled study. Br Med J 1985;291:109.

Martinsen EW. Benefits of exercise for the treatment of depression. Sports Med 1990;9:380-389.

Moller SE. Tryptophan and tyrosine availability and oral contraceptives. Lancet 1979;ii:472. (Letter)

Muldner VH, Zoller M. Antidepressive wirkung eines auf den. Lancet, 1990;336:392-395.

Nolen WA, van de Putte JJ, Dijken WA, Kamp JS. L-5HTP in depression resistant to re-uptake inhibitors. An open comparative study with tranylcypromine. Br J Psychiatry. 1985 Jul;147:16-22.
Abstract: L-5HTP and tranylcypromine were compared in an open, but controlled and cross-over study, in patients suffering from major depression; all were non-responders to several reuptake inhibitors, including oxaprotiline and fluvoxamine. After four unsuccessful sleep-deprivations, L-5HTP or tranylcypromine were given during four weeks in a crossover design. Of 17 patients given L-5HTP during both treatment periods, none responded, whereas of 26 patients treated with tranylcypromine, 15 responded. Thus, L-5HTP is not a therapeutically effective alternative in depressed patients who have not responded to reuptake inhibitors.

Nolen WA, van de Putte JJ, Dijken WA, Kamp JS, Blansjaar BA, Kramer HJ, Haffmans J. Treatment strategy in depression. II. MAO inhibitors in depression resistant to cyclic antidepressants: two controlled crossover studies with tranylcypromine versus L-5-hydroxytryptophan and nomifensine. Acta Psychiatr Scand. 1988 Dec;78(6):676-83.
Abstract: Antidepressants are ineffective in about 30% of the patients with major depression. Besides electroconvulsive therapy (ECT) and lithium, MAO inhibitors have been suggested as an alternative in such patients. In 2 controlled, partial crossover studies involving 47 patients with major depression who had already been treated unsuccessfully with at least 2 cyclic antidepressants, the effect of the MAO inhibitor tranylcypromine was studied. The first study was an open comparison with L-5-hydroxytryptophan (L-5HTP), the second study a double-blind comparison with nomifensine. Neither the patients treated with L-5HTP nor the patients treated with nomifensine, except one, improved. In contrast, tranylcypromine was effective in 50% of the patients. The depressions of the responders to tranylcypromine appeared to be more endogenous (according Newcastle Scale II) and of shorter duration than those of the non-responders. It is concluded that MAO inhibitors such as tranylcypromine are an effective alternative to ECT and lithium in patients with major depression who have failed to respond to cyclic antidepressants.

Reynolds E, et al. Folate deficiency in depressive illness. Br J Psychiatr 1970;117:287-292.

Rippere V. Some varieties of food intolerance in psychiatric patients: an overview. Nutr Health, 1984; 3(3):125-36.
Abstract: In this review it is stated that foods may cause many mental and behavioral symptoms by a variety of different mechanisms including cerebral allergy, food addictions, hypoglycemias, hyperinsulin reactions, caffeinism, hypersensitivity to chemical food additives, reactions to vasoactive amines in foods and reactions to neuropeptides formed from foods.

Rose DP, Cramp DG. Reduction of plasma tyrosine by oral contraceptives and oestrogens: a possible consequence of tyrosine aminotransferase induction. Clin Chem Acta 1970;29:49-53.

Russ CS, Hendricks TA, Chrisley BM, et al. Vitamin B-6 status of depressed and obsessive-compulsive patients. Nutr Rep Internat 1983;27:867-873.
Abstract: 7 depressed patients were studied for plasma pyridoxal phosphate levels. It was found that 4 of 7 depressed patients were B6 deficient, and none of the 7 controlled patients were. Using an enzyme stimulation test (EGOT), all of the depressed patients were deficient in B6 and none of the controls were.

Sabelli HC, Fawcett J, Gustovsky F, et al. Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements. J Clin Psychiatr 1986;47:66-70.

Salmaggi P, Bressa GM, Nicchia G, Coniglio M, La Greca P, Le Grazie C. Double-blind, placebo-controlled study of s-adenosyl-methionine in depressed post-menopausal women. Psychother Psychosom 1993;59(1):34-40.
Abstract: S-adenosyl-L-methionine (SAMe) is a naturally occurring substance which is a major source of methyl groups in the brain and has been found in previous studies to be an effective antidepressant. The aim of this study was to assess the efficacy of oral SAMe in the treatment of depressed postmenopausal women in a 30-day double-blind placebo-controlled randomized trial. During the course of the study, 80 women, between the ages of 45 and 59, who were diagnosed as having DSM-III-R major depressive disorder or dysthymia between 6 and 36 months following either natural menopause or hysterectomy, underwent 1 week of single-blind placebo washout, followed by 30 days of double-blind treatment with either SAMe 1,600 mg/day or placebo. There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study. Side effects were mild and transient.

van Praag H, de Hann S. Depression vulnerability and 5-hydroxytryptophan prophylaxis. Psychiatry Res 1980 Sep;3(1):75-83.
Abstract: Previous studies have indicated that (1) The group of vital (endogenous) depressions encompasses a subgroup with a central serotonin (5-hydroxytryptamine; 5-HT) deficiency. (2) Abolition of this deficiency--with the aid of 5-hydroxytryptophan (5-HTP), a 5-HT precursor, or clomipramine, a 5-HT reuptake inhibitor--leads to abatement of depressive symptoms. It therefore seems plausible that the suspected 5-HT deficiency contributes to the development of depressive symptoms instead of resulting from them. (3) In a majority of patients, the suspected 5-HT deficiency persists even when the depressive symptoms have disappeared and the medication has been discontinued. This suggested that the disturbed central 5-HT metabolism is not a direct causal, but a predisposing factor. If so, abolition of the suspected 5-HT deficiency, e.g., with the aid of 5-HTP, would be expected to have a prophylactic effect. As predicted, 5-HTP was found in the present study to reduce the relapse rate in recurrent vital depressions with both a unipolar and bipolar course. The prophylactic effect was most pronounced in patients with persistent disorders of central 5-HT metabolism; this observation, however, requires corroboration. 5-HTP prophylaxis is the first aimed (i.e., pathological substrate-oriented) type of chemoprophylaxis known in psychiatry.

van Praag HM. In search of the mode of action of antidepressants: 5-HTP/tyrosine mixtures in depression. Adv Biochem Psychopharmacol. 1984;39:301-314.
Abstract: For a long time, antidepressants have been considered to act via enhancement of central MA-ergic activity (due to reuptake or MAO inhibition). An alternative hypothesis holds that their action is based on down-regulation of MA-ergic activity (due to decrease in density or sensitivity of certain receptor populations). In this chapter I have discussed the likelihood of both hypotheses and have reached the conclusion that the first one is the more plausible. I have discussed the following arguments: The 5-HT precursor 5-HTP, which is transformed to 5-HT in the brain, has antidepressant properties. There are indications that the same holds true for tyrosine, a CA precursor transformed in the brain to DA and NE. I found evidence that the 5-HTP effects in depression are potentiated by tyrosine. Since activation rather than suppression of MA-ergic activity seems to be linked to antidepressant activity, it seems likely that the signs of decreased MA metabolism that has been demonstrated in certain types of depression are the expression of a primary metabolic deficit rather than a phenomenon secondary to receptor hyper-sensitivity. Further clinical studies of 5-HT/CA precursor combinations in depression are justified.

van Praag HM, Lemus C. Monoamine precursors in the treatment of psychiatric disorders. In: Nutrition and the Brain, Vol. 7, New York, Raven Press, Wurtman and Wurtman, 49-88, 1986.
Abstract: L-tryptophan seems to enhance the action of MAOI and Lithium in both manic and depressed patients.

van Praag HM. Studies in the mechanism of action of serotonin precursors in depression. Psychopharm Bull. 1984;20(3):599-602.
Abstract: This review article points out that the author has apparently conducted many double-blind studies using 200mg of L-5-hydroxytryptophan, 150mg carbidopa and/or tyrosine is effectie for the treatment for deprssion because it enhances both 5HT and catecholamine metabolism. When L-tryptophan is used by itself at 5 gms per day it only increases 5HT and tends not to work that well.

Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T, Ormiston S, Johnson R, Canick J, Brizendine L, Weingartner H. Antidepressant and cognition-enhancing effects of DHEA in major depression. Ann N Y Acad Sci. 1995 Dec 29;774:337-339.

Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T, Raum WJ, Ormiston S, Johnson R, Canick J, Brizendine L, Weingartner H. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry. 1997 Feb 1;41(3):311-318.
Abstract: Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA f1p4or DHEA-S levels were openly administered DHEA (30-90 mg/d x 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months: her depression ratings improved 48-72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland M, Brizendine L, Roberts E. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry. 1999 Apr;156(4):646-649.
Abstract: OBJECTIVE: This study was designed to assess possible antidepressant effects of dehydroepiandrosterone (DHEA), an abundant adrenocortical hormone in humans. METHOD: Twenty-two patients with major depression, either medication-free or on stabilized antidepressant regimens, received either DHEA (maximum dose = 90 mg/day) or placebo for 6 weeks in a double-blind manner and were rated at baseline and at the end of the 6 weeks with the Hamilton Depression Rating Scale. Patients previously stabilized with antidepressants had the study medication added to that regimen; others received DHEA or placebo alone. RESULTS: DHEA was associated with a significantly greater decrease in Hamilton depression scale ratings than was placebo. Five of the 11 patients treated with DHEA, compared with none of the 11 given placebo, showed a 50% decrease or greater in depressive symptoms. CONCLUSIONS: These results suggest that DHEA treatment may have significant antidepressant effects in some patients with major depression. Further, larger-scale trials are warranted.