Depression is a common emotional illness that varies widely in its intensity. Many of the natural treatments described in this section have been evaluated in people with major depression of mild to moderate intensity. This apparently contradictory language indicates a level of clinical depression that is significantly more intense than simply feeling "blue," but not as disabling as major depression of severe intensity, which usually requires hospitalization.
Typical symptoms of major depression of mild to moderate severity include depressed mood, lack of energy, sleep problems, anxiety, appetite disturbance, difficulty concentrating, and poor stress tolerance. Irritability can also be a sign of depression.
More severe depression includes markedly depressed mood complicated by symptoms such as slowed speech, slowed (or agitated) responses, markedly impaired memory and concentration, excessive (or diminished) sleep, significant weight loss (or weight gain), intense feelings of worthlessness and guilt, recurrent thoughts of suicide, and lack of interest in pleasurable activities. This form of clinical depression is a dangerous and excruciating illness. The emotional structure of the brain has frozen into a pattern of misery that cannot be altered by willpower, a change of scenery, or the most earnest efforts of friends. In a sense, the brain has locked up like a crashed computer.
One of the earliest successful treatments for major depression was shock therapy. This technique is in some ways analogous to rebooting a computer, and in cases of major depression, its effects were revolutionary. For the first time, a reliable way was available to bring people out of the depths of severe major depression.
However, shock treatment was overused at first and became unpopular as a result. The accidental discovery of antidepressant drugs provided a route with fewer interventions. The original antidepressants, known as MAO inhibitors, could bring people out from the depths of major depression as successfully as shock treatment. However, MAO inhibitors can cause serious and even fatal side effects. No one would ever think of using MAO inhibitors to treat mild to moderate depression.
Subsequently, antidepressants with progressively fewer side effects came on the market, but most of them still caused significant fatigue. Since fatigue is one of the most characteristic symptoms of mild to moderate depression, such medications were seldom found useful for anything other than severe depression. With the appearance of the selective serotonin reuptake inhibitor (SSRI) class of antidepressants, however, suddenly there was a practical option for depression that was less than catastrophic. Practically overnight, enormous numbers of people began taking Prozac and similar drugs for mild to moderate depression, as well as for the related, but more mild condition, known as dysthymia.
The big advantage of the SSRIs is that they usually don't cause severe fatigue. Many people find them to be entirely side effect-free. However, side effects are not uncommon and include sexual disturbances (such as impotence in men and the loss of the ability to experience an orgasm in women), insomnia, and nervousness. The antidepressant drug Wellbutrin is an option for people who have sexual side effects from SSRIs.
Alternative medicine offers numerous options for treating depression, but only one has strong scientific evidence behind it: the herb St. John's wort.
Numerous double-blind, placebo-controlled studies have examined the effectiveness of St. John's wort for the treatment of mild to moderate major depression, and most have found the herb more effective than placebo.1-6,123,135,155 In addition, at least 8 studies have found that St. John's wort is at least as effective as standard antidepressants, including fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa), and paroxetine (Paxil).7-9,124,125,136,137,148,192 A 2008 detailed review of 29 randomized, placebo controlled trials found that St. Johns wort was consistently more effective than placebo and equally effective to standard antidepressants.180 The total number of patients in these trials runs into the several thousands and compares favorably to the evidence-base for approved drugs. St. John’s wort has also shown a bit of promise for severe major depression, but the evidence is quite limited.137, 158
Note: St. John's wort alone should never be relied on for the treatment of severe depression.
Much has been made of two double-blind, placebo-controlled trials performed in the United States that failed to find St. John’s wort more effective than placebo for mild to moderate depression 5,123 However, two studies cannot overturn a body of positive research. Approximately 35% of double-blind studies involving pharmaceutical antidepressants have also failed to find the active agent significantly more effective than placebo.123 As if to illustrate this, in the more recent of the two trials in which St. John’s wort failed to prove effective, the drug sertraline (Zoloft) also failed to prove effective. The reason for these negative outcomes is not that Zoloft (or Prozac, or any other drug) does not work. Rather, statistical effects can easily hide the benefits of a drug, especially in a condition like depression where there is as a high placebo effect and no truly precise method for measuring symptoms.
St. John's wort seldom causes immediate side effects. However, it interacts adversely with a large number of critical medications and may present other safety issues as well. For more information, see the full St. John's Wort article.
There are a number of other herbs and supplements that may be helpful in depression, although the evidence for them is nowhere near as strong as that for St. John's wort.
In the body, the vitamin folate works in tandem with SAMe. Observational studies have suggested that depressed people have reduced folate levels, and a bit of evidence hints that folate supplements may help alleviate depression.90-96,162 In addition, people with particularly low folate levels may respond poorly to antidepressants.97,138
Based on these findings, a study examined the effects of combining folate with antidepressant treatment.98 This 10-week, double-blind, placebo-controlled trial of 127 people with severe major depression found that folate supplements at a dose of 500 mcg daily significantly improved the effectiveness of fluoxetine (Prozac) in female participants. Improvement in male participants was not significant, but blood tests conducted during the study suggest that higher intake of folate might be necessary for men.
Folate has also been paired with vitamin B12. In one study, over 900 older adults with mild depression were randomized to different treatment groups. One of the groups took folate (400 mcg) and B 12 (100 mcg) daily for 2 years. Folate and vitamin B 12 were no better than placebo at improving their depressive symptoms.184
For more information, including dosage and safety issues, see the full Folate article.
The supplement S-adenosylmethionine (SAMe) has been widely marketed for the treatment of depression, but the evidence to indicate that it works remains incomplete.
Several double-blind, placebo-controlled studies have found SAMe effective in relieving depression;70,71 however, most were small and poorly reported. In addition, many used injected SAMe rather than the oral supplement. Furthermore, a double-blind, placebo-controlled study of 133 depressed people, actually failed to find intravenous SAMe more effective than placebo.72 (Researchers managed to find some benefit to report by resorting to questionable statistical manipulation of the data.)
In addition to placebo-controlled studies, several trials have compared SAMe against antidepressant drugs in the tricyclic family.73-79,127 Again, many of these studies were poorly reported and designed, or they used injected SAMe rather than the oral supplement. Of the studies using oral SAMe, the best was a 6-week, double-blind trial of 281 people with mild depression.73 The results showed that SAMe was about as effective as the drug imipramine. However, the lack of a placebo group in this trial makes the results less than fully reliable. Other small studies have also compared the benefits of oral or intravenous SAMe to those of tricyclic antidepressants and have found generally equivalent results, although, again, poor reporting and inadequacies of study design (such as too limited a treatment interval) mar the meaningfulness of the outcomes.74-79
Researchers have also studied the effectiveness of oral SAMe in combination with antidepressants. Seventy-three patients with treatment-resistant major depression were randomized to take SAMe (800 mg twice daily) or a placebo.187 Both groups continued to take their selective serotonin reuptake inhibitor (SSRI). Adding SAMe to the treatment increased the rate at which patients responded to their antidepressant medication.
For more information, including dosage and safety issues, see the full S-adenosylmethionine article.
Ginkgo is used mainly for age-related mental decline such as that from Alzheimer's disease. However, during the studies on impaired mental function, researchers frequently observed improvements in mood and relief from symptoms of depression. This incidental discovery led scientists to investigate whether ginkgo might be useful as an antidepressant treatment.
One double-blind study, published in 1990, evaluated this effect in 60 people who suffered from depressive symptoms along with other signs of dementia.63 The results showed significant improvements among participants given ginkgo extract instead of placebo.
Another study followed 40 depressed people over the age of 50 who had not responded successfully to antidepressant treatment.64 Those who were given ginkgo showed an average drop of 50% in scores on the Hamilton Depression scale, whereas the placebo group showed only a 10% improvement.
In 1994 an interesting piece of research was reported that may shed light on the mechanism by which ginkgo may reduce depression.65 This study examined levels of serotonin receptors in rats of various ages. When older rats were given ginkgo, the level of serotonin-binding sites increased. However, the same effect was not observed in younger rats. The researchers theorized that ginkgo may block an age-related loss of serotonin receptors. Reduced receptors for serotonin may mean that the body needs more serotonin to produce a normal effect. Thus, ginkgo might improve the brain's ability to respond to serotonin (at least in older people). However, this is still highly speculative.
For more information, including dosage and safety issues, see the full Ginkgo article.
Phenylalanine is a naturally occurring amino acid that we all consume in our daily diets. There is some evidence that phenylalanine supplements may help reduce symptoms of depression.
Phenylalanine occurs in a right-hand and a left-hand form, known as D- and L-phenylalanine, respectively. Some studies have evaluated the D form, and others have evaluated a mixture of the D and L forms. Both formulations may provide some measure of relief for symptoms of depression. The mixed form (DLPA) is the one most commonly available in stores.
A 1978 study compared the effectiveness of D-phenylalanine against the antidepressant drug imipramine (taken in daily doses of 100 mg) and found them to be equally effective.48 A total of 60 people were randomly assigned to either one group or the other and followed for 30 days. D-phenylalanine worked more rapidly, producing significant improvement in only 15 days.
Another double-blind study followed 27 people, half of whom received DL-phenylalanine and the other half imipramine in higher doses of 150 mg to 200 mg daily.49,50 When the participants were reevaluated in 30 days, the two groups had improved by the same amount.
Unfortunately, there do not seem to have been any properly designed studies that compared phenylalanine to placebo. Until these are performed, phenylalanine cannot be considered a proven treatment for depression, but it is certainly promising.
For more information, including dosage and safety issues, see the full Phenylalanine article.
When the body sets about manufacturing serotonin, it first makes 5-hydroxytryptophan (5-HTP). The theory behind taking 5-HTP as a supplement is that providing the one-step-removed raw ingredient might raise serotonin levels.
There have been several preliminary studies of 5-HTP.54 The best of these trials was a 6-week study of 63 people given either 5-HTP (100 mg 3 times daily) or an antidepressant in the Prozac (fluvoxamine) family (50 mg 3 times daily).55 The results showed equal benefit between the supplement and the drug. Actually, 5-HTP worked a little better, but from a mathematical perspective, the difference was not statistically significant.
5-HTP caused fewer and less severe side effects than fluvoxamine. The only real complaint was occasional mild digestive distress.
For more information, including dosage and safety issues, see the full 5-hydroxytryptophan article.
It has been suggested that fish oil or the related substance ethyl-EPA may be helpful for people with depression.114,126,128,139,140,149,164,165,167,171, 196 For example, a 4-week, double-blind, placebo-controlled trial evaluated the potential benefits of fish oil in 20 individuals with depression.114 All but one of the participants were also taking standard antidepressants and had been for at least 3 months. By week 3 of the trial, the level of depression had improved to a significantly greater extent in the fish oil group than in placebo group. In addition, a double-blind, placebo-controlled study of 70 people with depression that did not respond well to drug treatment found that the addition of ethyl-EPA (a modified form of a primary ingredient of fish oil) improved the response.126 Similarly, a double-blind study that evaluated the anti-depressant effect of EPA plus fluoxetin (a popular anti-depressant medication) found the combination to be more effective than fluoxetine or EPA alone after 4 weeks of treatment.167
In another study, 40 people who had committed repeated acts of self-harm were given either fish oil or placebo for 12 weeks.161 The results indicated that fish oil supplementation markedly reduced measures of suicidality and well-being.
However, the best and most recent studies have failed to find benefit. A meta-analysis (formal statistical review of evidence) published in 2007 failed to find convincing evidence of benefit.164 The largest (77-participant) study in this review failed to find fish oil more effective than placebo for treatment of depression.140 Two subsequent studies enrolling a total of almost 300 people also failed to find benefit.163,165 And a third placebo-controlled study found no benefit for fish oil in improving “mental well-being” among 320 older adults without a diagnosis of depression.177
For more information, including dosage and safety issues, see the full Fish Oil article.
In seven out of eight studies reviewed, various forms of exercise proved beneficial for depression. Aerobic exercise, weight training, dancing, and racquetball all produced improvements in mood as compared to no exercise.
However, the findings of the one negative study reported in this review cast doubt on the others. In this trial, some participants exercised, while others took a course at school and didn't exercise at all. The results: equal benefits in both groups. This suggests that it may not be the exercise itself that is helping, but rather the general effects of participation in an organized activity.
Another feature of the positive studies also tends to cast doubt on the value of exercise per se in depression. You'd think that if it were exercise itself improving mood, the more effectively the participants exercised the greater the effect. However, no correlation was seen between how much participants increased their physical fitness and how significantly their depression improved.
Repetitive transcranial magnetic stimulation (rTMS) involves the application of low-frequency magnetic pulses to the brain. A growing body of evidence suggests that rTMS is helpful for depression.101-105,115-122,134,145-147,168,189
In a well-designed trial, for example, 70 people with major depression were given rTMS or sham rTMS in a double-blind setting over a period of 2 weeks.102 The results showed that participants who had received actual treatment experienced significantly greater improvement than did those receiving sham treatment. In a smaller trial involving 45 subjects, researchers found that rTMS is more effective than sham rTMS as an add-on treatment to anti-depressant medication in people with moderate to severe depression (including those with psychotic symptoms).189 In another trial involving 92 older patients whose depression has been linked to poor blood flow to the brain (so-called vascular depression), actual rTMS was significantly more effective than a sham rTMS. Benefits were more notable in younger patients.168
In a particularly persuasive piece of evidence, researchers pooled the results of 30 double-blind trials involving 1,164 depressed patients and determined that real rTMS is significantly more effective than sham (fake) rTMS.171
Studies suggest that rTMS may be an effective additional treatment for the 20%-30% of depressed people for whom conventional drug therapy is not successful.104,169,185 Another group of researchers pooled the results of 24 studies involving 1,092 patients and found rTMS to be more effective than sham for treatment-resistant depression.178
ECT (electroconvulsive therapy, or shock treatment) is often used for people who fall in this category, but rTMS may be an equally effective and less traumatic alternative.112,116,129
Like gingko, the supplement phosphatidylserine is used mainly for mental decline in the elderly, but it may also offer antidepressant benefits for seniors.68,69 Limited evidence hints that acetyl-L-carnitine may also offer benefits for seniors,108,109 as well as, potentially, for younger people.150
Diets low in vitamin B6 or vitamin B12 have been associated with symptoms of depression.110,111 While there is little direct evidence that taking these supplements can help depression, deficiencies of B 6 are common, and B 12 deficiencies occur more often with advancing age, so it may be a good idea to take these vitamins on general principles. Nonetheless, a randomized trial involving 299 men over the age of 75 found that a daily supplement containing a combination of vitamins B 6, B 12, and folate was no better than placebo at preventing depression over a 2-year period.175 The same was true in another study in which older adults with mild depression took folate (400 mcg) and B 12 (100 mcg) .184
In two reviews of 13 randomized trials with 4,394 patients, vitamin D3 supplements (oral or intramuscular injection) were not effective in reducing depressive symptoms when compared to placebo. However, some benefit was found in an analysis of 2 trials with patients who had more severe, clinically significant depression.193, 194
Other micronutrients are also commonly deficient in elderly populations. A small study among nursing home residents found that low levels of the mineral selenium was associated with depression. Moreover, 8 weeks of mineral supplementation tended to improve the mood of the most seriously depressed patients with low selenium levels.172
In a small double-blind, placebo-controlled study, tincture of lavender enhanced the antidepressant effectiveness of the drug imipramine.129 The hormone DHEA has shown some promise for depression.113,151-152
When depression is characterized by rapid mood changes, excessive sleeping and eating, a sense of leaden paralysis, and extreme sensitivity to negative life events, the condition is called atypical depression. A very small (15 participants) double-blind, placebo-controlled study found that chromium picolinate might be helpful for this form of depression;130 however, a much larger study failed to find convincing benefits.153
According to five preliminary double-blind studies, use of the herb saffron ( Crocus sativus) at 30 mg daily is more effective than placebo and equally effective as standard treatment for major depression.143,144,154,156, 159 However, all these studies were small and were performed by a single research group in Iran. Larger studies and independent confirmation will be necessary to determine whether saffron truly is effective for depression.
A double-blind study of 42 people with severe depression found no improvement with the supplement inositol.107 Similarly, use of multivitamin mixtures has failed to prove more effective than placebo.166
The herb Rhodiola rosea has also been studied as a treatment for depression.188 In a randomized trial, 89 people with mild to moderate depression received rhodiola extract 340 mg, rhodiola extract 680 mg, or a placebo for 6 weeks. Those in both rhodiola groups experienced an improvement in most of their depression symptoms, whereas those in the placebo group experienced no such benefit.
Music therapy was associated with short term improvements in depressive symptoms in a review of 5 randomized or quasi-randomized trials with 290 patients. In 5 trials, music therapy was added to standard care, and was found superior to standard care alone. The improvements were seen over a 3 month period. Positive effects were also seen in anxiety symptoms.197
One small trial involving 84 adults with major depression found that mindfulness-based cognitive therapy, a type of stress reduction program, was just as effective as antidepressants in reducing the chance of relapse.187 In addition, a 2011 systematic review that included 10 studies found evidence that mindfulness-based interventions may be beneficial for pain and depressive symptoms in patients suffering with chronic pain.190 The authors did highlight, though, the need for better quality studies.
Studies on acupuncture as a treatment for depression have shown mixed results. In a review of 20 trials involving 2,000 patients with major depression, researchers concluded that real acupunture's effectiveness was comparable to that of anti-depressants, but was no more effective than sham acupuncture for this population.183 Other studies have not found this benefit, though.100,160,174 There is some suggestion that combining acupuncture with fluoxetine may hasten the effect of the antidepressants and allow for a lower dose.181,182
Bright light therapy is standard treatment for seasonal affective disorder, but there has been some success in using it to treat nonseasonal depressive symptoms. In a small randomized trial with 122 adults, bright light therapy (with or without the antidepressant fluoxetine) improved depression severity scores. There were 4 groups in the trial that compared bright light therapy, sham bright light therapy, fluoxetine, and placebo. The most consistent positive effects were seen in those who used bright light therapy in combination with fluoxetine.195
Various herbs and supplements may interact adversely with drugs used to treat depression. For more information on this potential risk, see the individual drug article in the Drug Interactions section of this database.
1. Laakmann G, Schule C, Baghai T, et al. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(suppl):54-59.
2. Linde K, Ramirez G, Mulrow CD, et al. St. John's wort for depression—an overview and meta-analysis of randomised clinical trials. BMJ. 1996;313:253-258.
3. Philipp M, Kohnen R, Hiller KO. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. BMJ. 1999;319:1534-1539.
4. Schrader E, Meier B, Brattstrom A. Hypericum treatment of mild-moderate depression in a placebo-controlled study. A prospective, double-blind, randomized, placebo-controlled, multicentre study. Hum Psychopharmacol. 1998;13:163-169.
5. Shelton RC, Keller MB, Gelenberg A, et al. Effectiveness of St. John's wort in major depression: a randomized controlled trial. JAMA. 2001;285:1978-1986.
6. Kalb R, Trautmann-Sponsel RD, Kieser M. Efficacy and tolerability of hypericum extract WS 5572 versus placebo in mildly to moderately depressed patients. A randomized double-blind multicenter clinical trial. Pharmacopsychiatry. 2001;34:96-103.
7. Harrer G, Schmidt U, Kuhn U, et al. Comparison of equivalence between the St. John's wort extract LoHyp-57 and fluoxetine. Arzneimittelforschung. 1999;49:289-296.
8. Schrader E. Equivalence of St John's wort extract (Ze 117) and fluoxetine: a randomized, controlled study in mild-moderate depression. Int Clin Psychopharmacol. 2000;15:61-68.
9. Brenner R, Azbel V, Madhusoodanan S, et al. Comparison of an extract of hypericum (LI 160) and sertraline in the treatment of depression: a double-blind, randomized pilot study. Clin Ther. 2000;22:411-419.
10. Suzuki O, Katsumata Y, Oya M, et al. Inhibition of monoamine oxidase by hypericin. Planta Med. 1984;50:272-274.
11. Bladt S, Wagner H. Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol. 1994;7(suppl 1):S57-S59.
12. Thiede HM, Walper A. Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol. 1994;7(suppl 1):S54-S56.
13. Muller WE, Rossol R. Effects of hypericum extract on the expression of serotonin receptors . J Geriatr Psychiatry Neurol. 1994;7(suppl 1):S63-S64.
14. Muller WE, Kasper S, Volz HP, et al. Hypericum extract (LI160) as an herbal antidepressant. Pharmacopsychiatry. 1997;30(suppl 2):71-134.
15. Laakmann G, Schule C, Baghai T, et al. St. John's wort in mild to moderate depression: the relevance of hyperforin for the clinical efficacy. Pharmacopsychiatry. 1998;31(suppl):54-59.
48. Heller B. Pharmacological and clinical effects of D-phenylalanine in depression and Parkinson's disease. In: Mosnaim AD, Wolf ME, eds. Noncatecholic Phenylethylamines. Part 1. New York, NY: Marcel Dekker; 1978:397-417.
49. Beckmann H, Athen D, Olteanu M, et al. DL-phenylalanine versus imipramine: a double-blind controlled study. Arch Psychiatr Nervenkr. 1979;227:49-58.
50. Beckmann H. Phenylalanine in affective disorders. Adv Biol Psychiatry. 1983;10:137-147.
54. Byerley WF, Judd LL, Reimherr FW, et al. 5-hydroxytryptophan: a review of its antidepressant efficacy and adverse effects. J Clin Psychopharmacol. 1987;7:127-137.
55. Poldinger W, Calanchini B, Schwarz W. A functional-dimensional approach to depression: serotonin deficiency as a target syndrome in a comparison of 5-hydroxytryptophan and fluvoxamine. Psychopathology. 1991;24:53-81.
63. Eckmann F. Cerebral insufficiency—treatment with Ginkgo-biloba extract. Time of onset of effect in a double-blind study with 60 inpatients [translated from German]. Fortschr Med. 1990;108:557-560.
64. Schubert H, Halama P. Depressive episode primarily unresponsive to therapy in elderly patients: efficacy of Ginkgo biloba extract EGb 761 in combination with antidepressants [translated from German]. Geriatr Forsch. 1993;3:45-53.
65. Huguet F, Drieu K, Piriou A. Decreased cerebral 5-HT 1A receptors during ageing: reversal by Ginkgo biloba extract (EGv 761). J Pharm Pharmacol. 1994;46:316-318.
68. Maggioni M, Picotti GB, Bondiolotti GP, et al. Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand. 1990;81:265-270.
69. Brambilla F, Maggioni M, Panerai AE, et al. Beta-endorphin concentration in peripheral blood mononuclear cells of elderly depressed patients—effects of phosphatidylserine therapy. Neuropsychobiology. 1996;34:18-21.
70. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.
71. Echols JC, Naidoo U, Salzman C. SAMe (S-adenosylmethionine). Harv Rev Psychiatry. 2000;8:84-90.
72. Delle Chiaie R, Pancheri P. Combined analysis of two controlled, multicentric, double blind studies to assess efficacy and safety of sulfo-adenosyl-methionine (SAMe) vs. placebo (MC1) and SAMe vs. clomipramine (MC2) in the treatment of major depression [in Italian; English abstract]. G Ital Psicopatol. 1999;5:1-16.
73. Delle Chiaie R, Pancheri P, Scapicchio P. MC3: multicentre, controlled efficacy and safety trial of oral S-adenosyl-methionine (SAMe) vs. oral imipramine in the treatment of depression [abstract]. Int J Neuropsychopharmcol. 2000;3(suppl 1):S230.
74. Bell KM, Plon L, Bunney WE Jr, et al. S-adenosylmethionine treatment of depression: a controlled clinical trial. Am J Psychiatry. 1988;145:1110-1114.
75. De Vanna M, Rigamonti R. Oral S-adenosyl-L-methionine in depression. Curr Ther Res. 1992;52:478-485.
76. Bell KM, Potkin SG, Carreon D, et al. S-adenosylmethionine blood levels in major depression: changes with drug treatment. Acta Neurol Scand Suppl. 1994;154:15-18.
77. Echols JC, Naidoo U, Salzman C. SAMe (S-adenosylmethionine). Harv Rev Psychiatry. 2000;8:84-90.
78. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepressant: meta-analysis of clinical studies. Acta Neurol Scand Suppl. 1994;154:7-14.
79. Delle Chiaie R, Pancheri P, Scapicchio P. MC4: multicentre, controlled efficacy and safety trial of intramuscular S-adenosyl-methionine (SAMe) vs. oral imipramine I the treatment of depression [abstract]. Int J Neuropsychopharmcol. 2000;3(suppl 1):S230.
90. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55:145-149.
91. Passeri M, Cucinotta D, Abate G, et al. Oral 5'-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano). 1993;5:63-71.
92. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392-395.
93. Heseker H, Kubler W, Pudel V, et al. Psychological disorders as early symptoms of a mild-to-moderate vitamin deficiency. Ann N Y Acad Sci. 1992;669:352-357.
94. Crellin R, Bottiglieri T, Reynolds EH. Folates and psychiatric disorders: clinical potential. Drugs. 1993;45:623-636.
95. Botez MI. Folate deficiency and neurological disorders in adults. Med Hypotheses. 1976;2:135-140.
96. Coppen A, Swade C, Jones SA, et al. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989;16:103-107.
97. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130.
98. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial. J Affect Disord. 2000;60:121-130.
99. Meyer T, Broocks A. Therapeutic impact of exercise on psychiatric diseases: guidelines for exercise testing and prescription. Sports Med. 2000;30:269-279.
100. Eich H, Agelink MW, Lehmann E, et al. Acupuncture in patients with minor depressive episodes and generalized anxiety. Results of an experimental study [in German; English abstract]. Fortschr Neurol Psychiatr. 2000;68:137-144.
101. Pascual-Leone A, Rubio B, Pallardo F, et al. Rapid-rate transcranial magnetic stimulation of the left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996;348:233-237.
102. Klein E, Kreinin I, Chistyakov A, et al. Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study. Arch Gen Psychiatry. 1999;56:315-320.
103. George MS, Wassermann EM, Kimbrell TA, et al. Mood improvement following daily left prefrontal repetitive transcranial magnetic stimulation in patients with depression: a placebo-controlled crossover trial. Am J Psychiatry. 1997;154:1752-1756.
104. Berman RM, Narasimhan M, Sanacora, et al. A randomized clinical trial of repetitive transcranial magnetic stimulation in the treatment of major depression. Biol Psychiatry. 2000;47:332-337.
105. Padberg F, Zwanzger P, Thoma H, et al. Repetitive transcranial magnetic stimulation (rTMS) in pharmacotherapy-refractory major depression: comparative study of fast, slow and sham rTMS. Psychiatry Res. 1999;88:163-171.
106. Boutros NN, Gueorguieva R, Hoffman RE, et al. Lack of a therapeutic effect of a 2-week sub-threshold transcranial magnetic stimulation course for treatment-resistant depression. Psychiatry Res. 2002;113:245-254.
107. Nemets B, Mishory A, Levine J, et al. Inositol addition does not improve depression in SSRI treatment failures. J Neural Transm. 1999;106:795-798.
108. Bella R, Biondi R, Raffaele R, et al. Effect of acetyl-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res. 1990;10:355-360.
109. Garzya G, Corallo D, Fiore A, et al. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res. 1990;16:101-106.
110. Bell IR, Edman JS, Morrow FD, et al. B complex vitamin patterns in geriatric and young adult inpatients with major depression. J Am Geriatr Soc. 1991;39:252-257.
111. Zucker DK, Livingston RL, Nakra R, et al. B 12 deficiency and psychiatric disorders: case report and literature review. Biol Psychiatry. 1981;16:197-205.
112. Janicak PG, Dowd SM, Martis B, et al. Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial. Biol Psychiatry. 2002;51:659-667.
113. Wolkowitz OM, Reus VI, Keebler A, et al. Double-blind treatment of major depression with dehydroepiandrosterone. Am J Psychiatry. 1999;156:646-649.
114. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159:477-479.
115. Garcia-Toro M, Mayol A, Arnillas H, et al. Modest adjunctive benefit with transcranial magnetic stimulation in medication-resistant depression. J Affect Disord. 2001;64:271-275.
116. Grunhaus L, Dannon PN, Schreiber S, et al. Repetitive transcranial magnetic stimulation is as effective as electroconvulsive therapy in the treatment of nondelusional major depressive disorder: an open study. Biol Psychiatry. 2000;47:314-324.
117. Hasey G. Transcranial magnetic stimulation in the treatment of mood disorder: a review and comparison with electroconvulsive therapy. Can J Psychiatry. 2001;46:720-727.
118. Kirkcaldie MT, Pridmore SA, Pascual-Leone A. Transcranial magnetic stimulation as therapy for depression and other disorders. Aust N Z J Psychiatry. 1997;31:264-272.
119. Manes F, Jorge R, Morcuende M, et al. A controlled study of repetitive transcranial magnetic stimulation as a treatment of depression in the elderly. Int Psychogeriatr. 2001;13:225-231.
120. Pridmore S. Substitution of rapid transcranial magnetic stimulation treatments for electroconvulsive therapy treatments in a course of electroconvulsive therapy. Depress Anxiety. 2000;12:118-123.
121. Szuba MP, O'Reardon JP, Rai AS, et al. Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression. Biol Psychiatry. 2001;50:22-27.
122. Teneback CC, Nahas Z, Speer AM, et al. Changes in prefrontal cortex and paralimbic activity in depression following two weeks of daily left prefrontal TMS. J Neuropsychiatry Clin Neurosci. 1999;11:426-435.
123. Hypericum Depression Trial Study Group. Effect of Hypericum perforatum (St. John’s wort) in major depressive disorder: a randomized controlled trial. JAMA. 2002;287:1807-1814.
124. Behnke K, Jensen GS, Graubaum HJ, et al. Hypericum perforatum versus fluoxetine in the treatment of mild to moderate depression. Adv Ther. 2002;19:43-52.
125. van Gurp G, Meterissian GB, Haiek LN, et al. St John's wort or sertraline? Randomized controlled trial in primary care. Can Fam Physician. 2002;48:905-912.
126. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59:913-919.
127. Pancheri P, Scapicchio P, Chiaie RD. A double-blind, randomized parallel-group, efficacy and safety study of intramuscular S-adenosyl-L-methionine 1,4-butanedisulphonate (SAMe) versus imipramine in patients with major depressive disorder. Int J Neuropsychopharmacol. 2002;5:287-294.
128. Marangell LB, Martinez JM, Zboyan HA, et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003;160:996-998.
129. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill tincture and imipramine in the treatment of mild to moderate depression: a double-blind, randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
130. Davidson JR, Abraham K, Connor KM, et al. Effectiveness of chromium in atypical depression: a placebo-controlled trial. Biol Psychiatry. 2003;53:261-264.
131. Sharma K, Kushwaha H, Sharma, S. A placebo-controlled trial on the efficacy of Mentat in managing depressive disorders. Probe. 1993;33:26-31.
132. Janakiramaiah N, Gangadhar BN, Naga Venkatesh Murthy PJ, et al. Antidepressant efficacy of Sudarshan Kriya Yoga (SKY) in melancholia: a randomized comparison with electroconvulsive therapy (ECT) and imipramine. J Affect Disord. 2000;57:255-259.
133. Field T. Massage therapy. Med Clin North Am. 2002;86:163-171.
134. Dolberg OT, Dannon PN, Schreiber S, et al. Transcranial magnetic stimulation in patients with bipolar depression: a double blind, controlled study. Bipolar Disord. 2002;4:94-95.
135. Uebelhack R, Gruenwald J, Graubaum HJ, et al. Efficacy and tolerability of Hypericum extract STW 3-VI in patients with moderate depression: a double-blind, randomized, placebo-controlled clinical trial. Adv Ther. 2004;21:265-75.
136. Bjerkenstedt L, Edman GV, Alken RG, et al. Hypericum extract LI 160 and fluoxetine in mild to moderate depression, A randomized, placebo-controlled multi-center study in outpatients. Eur Arch Psychiatry Clin Neurosci. 2004 Nov 12. [Epub ahead of print]
137. Szegedi A, Kohnen R, Dienel A, Kieser M. Acute treatment of moderate to severe depression with hypericum extract WS 5570 (St John's wort): randomised controlled double blind non-inferiority trial versus paroxetine. BMJ. 2005 Feb 11. [Epub ahead of print]
138. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B 12, and homocysteine in major depressive disorder, part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004;65:1090-1095.
139. Silvers KM, Woolley CC, Hamilton FC, et al. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 2005;72:211-218.
140. Su KP, Huang SY, Chiu CC, et al. Omega-3 fatty acids in major depressive disorder—a preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13:267-271.
141. Silvers KM, Woolley CC, Hamilton FC, et al. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 2005;72:211-218.
142. Nowak G, Siwek M, Dudek D, et al. Effect of zinc supplementation on antidepressant therapy in unipolar depression: a preliminary placebo-controlled study. Pol J Pharmacol. 2003;55: 1143-1147.
143. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression: a pilot double-blind randomized trial. BMC Complement Altern Med. 2004 Sep 2. [Epub ahead of print]
144. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression: a double-blind, randomized pilot trial. J Ethnopharmacol. 2005;97:281-284.
145. Kosel M, Frick C, Lisanby SH, et al. Magnetic seizure therapy improves mood in refractory major depression. Neuropsychopharmacology. 2003 Aug 27. [Epub ahead of print]
146. Kauffmann CD, Cheema MA, Miller BE. Slow right prefrontal transcranial magnetic stimulation as a treatment for medication-resistant depression: a double-blind, placebo-controlled study. Depress Anxiety. 2004;19:59-62.
147. Fitzgerald PB, Brown TL, Marston NA, et al. Transcranial magnetic stimulation in the treatment of depression: a double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2003;60:1002-1008.
148. Gastpar M, Singer A, Zeller K. Comparative efficacy and safety of a once-daily dosage of hypericum extract STW3-VI and citalopram in patients with moderate depression: a double-blind, randomised, multicentre, placebo-controlled study. Pharmacopsychiatry. 2006;39:66-75.
149. Frangou S, Lewis M, McCrone P, et al. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: randomised double-blind placebo-controlled study. Br J Psychiatry. 2006;188:46-50.
150. Zanardi R, Smeraldi E. A double-blind, randomised, controlled clinical trial of acetyl-l-carnitine vs. amisulpride in the treatment of dysthymia. Eur Neuropsychopharmacol. 2005 Nov 25. [Epub ahead of print]
151. Schmidt PJ, Daly RC, Bloch M, et al. Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression. Arch Gen Psychiatry. 2005;62:154-62.
152. Rabkin JG, McElhiney MC, Rabkin R, et al. Placebo-controlled trial of dehydroepiandrosterone (DHEA) for treatment of nonmajor depression in patients with HIV/AIDS. Am J Psychiatry. 2006;163:59-66.
153. Docherty JP, Sack DA, Roffman M, et al. A double-blind, placebo-controlled, exploratory trial of chromium picolinate in atypical depression: effect on carbohydrate craving. J Psychiatr Pract. 2005;11:302-314.
154. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression: a double-blind, randomized and placebo-controlled trial. Phytother Res. 2005;19:148-51.
155. Kasper S, Anghelescu I, Szegedi A, et al. Superior efficacy of St Johns wort extract WS® 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial. BMC Med. 2006 Jun 23. [Epub ahead of print]
156. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression: A double-blind, randomized and placebo-controlled trial. Phytomedicine. 2006 Sep 14. [Epub ahead of print]
157. Zhang ZJ, Kang WH, Li Q, et al. The beneficial effects of the herbal medicine Free and Easy Wanderer Plus (FEWP) for mood disorders: Double-blind, placebo-controlled studies. J Psychiatr Res. 2006 Sep 28. [Epub ahead of print]
158. Anghelescu IG, Kohnen R, Szegedi A, et al. Comparison of hypericum extract WS® 5570 and paroxetine in ongoing treatment after recovery from an episode of moderate to severe depression: results from a randomized multicenter study. Pharmacopsychiatry. 2006;39:213-219.
159. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L and fluoxetine in the treatment of depressed outpatients: A pilot double-blind randomized trial. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Dec 14. [Epub ahead of print]
160. Allen JJ, Schnyer RN, Chambers AS, et al. Acupuncture for depression: a randomized controlled trial. J Clin Psychiatry. 2006;67:1665-1673.
161. Hallahan B, Hibbeln JR, Davis JM, et al. Omega-3 fatty acid supplementation in patients with recurrent self-harm: single-centre double-blind randomised controlled trial. Br J Psychiatry. 2007;190:118-122.
162. Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007;61:631-637.
163. Grenyer BF, Crowe T, Meyer B, et al. Fish oil supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Jun 19. [Epub ahead of print]
164. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68:1056-1061.
165. Rogers PJ, Appleton KM, Kessler D, et al. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial. Br J Nutr. 2007 Oct 24. [Epub ahead of print]
166. America A, Milling LS. The efficacy of vitamins for reducing or preventing depression symptoms in healthy individuals: natural remedy or placebo? J Behav Med. 2007 Nov 13. [Epub ahead of print]
167. Jazayeri S, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008;42:192-198.
168. Jorge RE, Moser DJ, Acion L, et al. Treatment of vascular depression using repetitive transcranial magnetic stimulation. Arch Gen Psychiatry. 2008;65:268-276.
169. Bretlau LG, Lunde M, Lindberg L, et al. Repetitive transcranial magnetic stimulation (rTMS) in combination with escitalopram in patients with treatment-resistant major depression. A double-blind, randomised, sham-controlled trial. Pharmacopsychiatry. 2008;41:41-47.
170. Coelho HF, Boddy K, Ernst E. Massage therapy for the treatment of depression: a systematic review. Int J Clin Pract. 2008;62:325-333.
171. Schutter DJ. Antidepressant efficacy of high-frequency transcranial magnetic stimulation over the left dorsolateral prefrontal cortex in double-blind sham-controlled designs: a meta-analysis. Psychol Med. 2008 Apr 30.
172. Gosney MA, Hammond MF, Shenkin A, et al. Effect of micronutrient supplementation on mood in nursing home residents. Gerontology. 2008 May 8.
173. Butler LD, Waelde LC, Hastings TA, et al. Meditation with yoga, group therapy with hypnosis, and psychoeducation for long-term depressed mood: a randomized pilot trial. J Clin Psychol. 2008 May 5.
174. Wang H, Qi H, Wang BS, et al. Is acupuncture beneficial in depression: A meta-analysis of 8 randomized controlled trials? J Affect Disord. 2008 Jun 10.
175. Ford AH, Flicker L, Thomas J, et al. Vitamins B 12, B 6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial. J Clin Psychiatry. 2008 Jun 10.
176. Li LT, Wang SH, Ge HY, et al. The beneficial effects of the herbal medicine Free and Easy Wanderer Plus (FEWP) and fluoxetine on post-stroke depression. J Altern Complement Med. 2008 Aug 23.
177. van de Rest O, Geleijnse JM, Kok FJ, et al. Effect of fish-oil supplementation on mental well-being in older subjects: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr. 2008;88:706-713.
178. Lam RW, Chan P, Wilkins-Ho M, et al. Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and metaanalysis. Can J Psychiatry. 2008;53:621-631.
179. Jorm AF, Morgan AJ, Hetrick SE. Relaxation for depression. Cochrane Database Syst Rev. 2008;CD007142.
180. Linde K, Berner MM, Kriston L. St John's wort for major depression. Cochrane Database Syst Rev. 2008;CD000448.
181. Zhang WJ, Yang XB, Zhong BL. Combination of acupuncture and fluoxetine for depression: a randomized, double-blind, sham-controlled trial. J Altern Complement Med. 2009;15:837
182. Duan DM, Tu Y, Chen LP, et al. Efficacy evaluation for depression with somatic symptoms treated by electroacupuncture combined with Fluoxetine. J Tradit Chin Med. 2009;29(3):167.
183. Zhang ZJ, Chen HY, Yip KC, Ng R, Wong VT. The effectiveness and safety of acupuncture therapy in depressive disorders: systematic review and meta-analysis. J Affect Disord. 2010;124(1-2):9-21.
184. Walker JG, Mackinnon AJ, Batterham P, et al. Mental health literacy, folic acid and vitamin B12, and physical activity for the prevention of depression in older adults: randomised controlled trial. Br J Psychiatry. 2010;197(1):45-54.
185. Sobiś J, Jarzab M, Hese RT, et al. Therapeutic efficacy assessment of weak variable magnetic fields with low value of induction in patients with drug-resistant depression. J Affect Disord. 2010;123(1-3):321-326.
186. Segal ZV, Bieling P, Young T, et al. Antidepressant monotherapy vs sequential pharmacotherapy and mindfulness-based cognitive therapy, or placebo, for relapse prophylaxis in recurrent depression. Arch Gen Psychiatry. 2010;67(12):1256-1264.
187. Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry. 2010;167(8):942-948.
188. Darbinyan V, Aslanyan G, Amroyan E, Gabrielyan E, Malmström C, Panossian A. Clinical trial of Rhodiola rosea L. extract SHR-5 in the treatment of mild to moderate depression. Nord J Psychiatry. 2007;61(5):343-348.
189. Ray S, Nizamie SH, Akhtar S, Praharaj SK, Mishra BR, Zia-ul-Haq M. Efficacy of adjunctive high frequency repetitive transcranial magnetic stimulation of left prefrontal cortex in depression: a randomized sham controlled study. J Affect Disord. 2011;128(1-2):153-159.
190. Chiesa A, Serretti A. Mindfulness-based interventions for chronic pain: a systematic review of the evidence. J Altern Complement Med. 2011;17(1):83-93.
192. Singer A, Schmidt M, Hauke W, Stade K. Duration of response after treatment of mild to moderate depression with Hypericum extract STW 3-VI, citalopram and placebo: a reanalysis of data from a controlled clinical trial. Phytomedicine. 2011;18(8-9):739-742.
193. Shaffer JA, Edmondson D, et al. Vitamin D supplementation for depressive symptoms: A systematic review and meta-analysis of randomized controlled trials. 2014;76(3):190-196.
194. Li G, Mbuagbaw L, et al. Efficacy of vitamin D supplementation in depression in adults: a systematic review. J Clin Endocrinol Metab. 2014;99(3):757-767.
195. Lam RW, Levitan RD, Michalak EE, et al. Efficacy of bright light treatment, fluoxetine, and the combination in patients with nonseasonal major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2016;73(1):56-63.
196. Appleton KM, Sallis HM, Perry R, Ness AR, Churchill R. Omega-3 fatty acids for depression in adults. Cochrane Databse Syst Rev. 2015;(11):CD004692.
197. Aalbers S, Fusar-Poli L, Freeman RE, et al. Music therapy for depression.Cochrane Database Syst Rev. 2017;11:CD004517.
198. Panahi Y, Badeli R, et al. A randomized controlled trial of 6-week Chlorella vulgaris supplementation in patients with major depressive disorder. Complement Ther Med. 2015;23(4):598-602.
Last reviewed December 2015 by EBSCO CAM Review Board
Last Updated: 3/25/2019