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ST. JOHN’S WORT is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors) are limited (SOR: A, 1 systematic review).
A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects.
Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety.
N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don’t appear effective in treating major depressive disorder (SOR: A, 1 systematic review.)
Evidence summary
TABLE W1 summarizes study results and recommendations for nutritional therapies for depression.1-16
St. John’s wort works as well as standard antidepressants
A recent Cochrane review suggested that St. John’s wort is more effective than placebo in patients with mild to moderate depression and as effective as standard antidepressants.1
Other supplements also have benefits
A systematic review of 4 small randomized controlled trials (RCTs) suggested that saffron (30 mg) is superior to placebo in treating short-term depression (6 weeks). Treatment and outcomes were equivalent to fluoxetine and imipramine.2 A later RCT yielded results consistent with the systematic review.3
Combined lavender tincture (60 drops per day) and imipramine were more effective than imipramine alone in 1 small RCT.4
Borage, a traditional Persian medicine, was superior to placebo in reducing depressive symptoms in 1 small RCT.2
Dan zhi xiao yao, a traditional Chinese medicine, was as effective as the tricyclic anti-depressant maprotiline in 1 small RCT.2
Three RCTs suggested that folate may be used to supplement conventional treatments for depression, but it isn’t clear whether this would help patients with normal folate levels.5
A meta-analysis of 13 controlled clinical trials and a later systematic review of 11 articles including 2 RCTs concluded that SAMe is more effective than placebo and as efficacious as tricyclic antidepressants in treating major depression in adults. However, further trials are needed to answer questions about absorption, mechanism of action, and bioavailability.6,7
Tryptophan’s benefit comes with risk
In a Cochrane review of 2 RCTs, tryptophan and 5-HTP were superior to placebo in alleviating symptoms of depression. However, some published case reports have linked tryptophan use to potentially fatal eosinophilia-myalgia syndrome.8
No clear evidence for inositol or n-3 PUFAs
A Cochrane review of 4 small double-blind RCTs investigating inositol as a nutritional supplement in depression treatment failed to find clear evidence of therapeutic benefit.9
Three RCTs demonstrated significantly higher red blood cell membrane levels of n-3 PUFAs in nondepressed patients compared with depressed patients.10 However, a systematic review of 12 RCTs failed to demonstrate any benefit of n-3 PUFA supplementation over placebo in treating depressed mood.11 The authors concluded that larger trials are needed to demonstrate efficacy because of marked heterogeneity among the RCTs.
Safety issues. A recent Cochrane review found fewer adverse effects for St. John’s wort than tricyclic antidepressants.1 The most common adverse reactions were sensitivity to light, skin symptoms, gastrointestinal symptoms, and agitation. Data comparing St. John’s wort with newer antidepressants are lacking.
St. John’s wort does have pharmacokinetic interactions and should not be taken concurrently with other antidepressants, immunosuppressants, anti-HIV drugs, cou-marin-type anticoagulants, or certain antineoplastic agents.17
Reviews of meta-analyses, case reports, population studies, RCTs, and other literature have reported virtually no adverse effects for PUFAs; 18 trials investigating saffron, lavender, borage, dan zhi xiao yao, folate, SAMe, and inositol also reported no safety concerns. However, the size and duration of these studies limit their ability to detect significant problems.2,5,6,9 As previously noted, concerns exist regarding an association between tryptophan and eosinophilia-myalgia syndrome.8
Recommendations
The World Federation of Societies of Biological Psychiatry doesn’t recommend St. John’s wort for moderate to severe depression, but suggests it can be considered for treating mild to moderate depressive episodes provided the prescriber considers potential pharmacokinetic interactions with other medications and understands possible variations in purity and potency of extracts.19 The Federation also states that St. John’s wort is an alternative for patients reluctant to take traditional antidepressants.
TABLE W1
What the studies say about nutritional therapies for depression
| Supplement | Study type | Number of subjects | Comparison group | Outcome measure | Results | Conclusion | SOR |
|---|---|---|---|---|---|---|---|
| Borage (Echium amoenum) | 1 small RCT | 352,16 | Placebo | HAM-D | Improved HAM-D scores significantly at week 4 (borage 18. 3±3. 9 vs placebo 21. 9±3. 9; t=2. 51; P=. 02); no significant difference at Week 62,16 | Superior to placebo in reducing symptoms of depression | B |
| Dan zhi xiao yao | 1 small RCT | 632 | Maprotiline | HAM-D, SDS, SAS, scale for traditional Chinese medicine syndrome and symptom differentiation | 87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) | As effective as maprotiline in treating depression | B |
| Folate | Cochrane review of 3 RCTs | 2475 | Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels) | HAM-D | Superior to placebo (NNT=5, defined as 50% reduction in HAM-D); comparable to trazodone (RR=0. 97; 95% CI, 0. 14-2. 01)7 | May have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levels | A |
| Inositol | Cochrane review of 4 RCTs | 1419 | Studies 1-3: placebo plus conventional antidepressants Study 4: placebo only | HAM-D, MADRS | Pooled estimate of effect of all 3 studies (SMD= -0. 08; 95% CI, -0. 45 to 0. 30) | No clear evidence of therapeutic benefit | A |
| Lavender (Lavandula angustifolia) | 1 small RCT | 454 | Imipramine | HAM-D | Imipramine plus lavender showed significant effect compared with imipramine alone (f=26. 87; Df=3. 01; P<. 0001) | Synergistic effect suggested when used with imipramine | B |
| n-3 long-chain polyunsaturated fatty acids | Systematic review including 3 RCTs; 10 meta-analysis of 12 RCTs11 | 10210 103211 | Various comparison groups included | Serum SFAs, MUFAs, PUFAs; RBC membrane levels n-3 PUFAs2 HAM-D, BDI3 | Systematic review:10 Study 1: n=30; ES=3. 61 Study 2: n=24; ES=1. 2 Study 3: n=48; ES=2. 43 Meta-analysis:11 Pooled ES=0. 13; 95% CI, 0. 01-0. 25 | Significantly higher RBC membrane levels of n-3 PUFAs in nondepressed vs depressed patients10 No significant effect for supplementation11 Larger trials with adequate power needed2,3 | A |
| S-adenosyl-methionine (SAMe) | Meta-analysis of 13 RCTs,6 systematic review including 2 RCTs7 | 3996 787 | Placebo and conventional antidepressants | HAM-D | NNT=2. 5 for HAM-D decrease of >25%; 6 NNT=6. 25 for HAM-D decrease of >50%6 | May have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7 | A |
| Saffron (Crocus sativus) | Systematic review of 4 small RCTs, 1 later RCT | 3012 4013 4014 4015 403 | Imipramine12 Placebo13,15 Fluoxetine5,14 | HAM-D | Systematic review: Study 1: imipramine and saffron equally efficacious (f=2. 91; P=. 09)12 Study 2: Improved HAM-D scores: -12. 20±4. 67 (saffron) vs -5. 10±4. 71 (placebo) (P<. 0001)13 Study 3: Improved HAM-D scores: saffron petal -12. 00±4. 10; fluoxetine -13. 50±4. 91; difference between 2 treatments not significant (P=. 27)14 Study 4: Improved HAM-D scores: -14. 01±5. 53 (saffron petal) vs -5. 05±4. 63 (placebo) (P<. 0001)15 Study 5:5 NNT=10 | Efficacy of extract and petal suggested to treat mild to moderate depression Large-scale trials are warranted | B |
| St. John’s wort (Hypericum perforatum L. ) | Cochrane review of 29 RCTs | 54891 | SSRIs, tri/tetracyclic antidepressants, placebo | Responder rate ratio | St. John’s wort vs placebo: 9 larger trials: RR=1. 28; 95% CI, 1. 10-1. 491 9 smaller trials: RR=1. 87; 95% CI, 1. 22-2. 871 St. John’s wort vs SSRIs: 12 trials: RR=1. 00; 95% CI, 0. 90-1. 111 St. John’s wort vs tricyclics: 5 trials: RR=1. 02; 95% CI, 0. 90-1. 151 | Effective for treating mild to moderate depression | A |
| Tryptophan and 5-hydroxy-tryptophan (5-HTP) | Cochrane review of 2 RCTs | 648 | Placebo | HAM-D | NNT=2. 78 vs placebo (OR=4. 1; 95% CI, 1. 28-13. 15 | Superior to placebo Insufficient evidence regarding safety | A |
| BDI, Beck Depression Inventory; CI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; HAM-D, Hamilton Depression Rating Scale; MADRS, Mont-gomery-Asberg Depression Rating Scale; MUFAs, monounsaturated fatty acids; n-3 PUFAs, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; OR, odds ratio; PUFAs, polyunsaturated fatty acids; RBC, red blood cell; RCT, randomized controlled trial; RR, relative risk; SAS, self-rating anxiety scale; SDS, self-rating depression scale; SFAs, saturated fatty acids; SMD, standard weighted mean difference; SOR, strength of recommendation; SSRI, selective serotonin reuptake inhibitor. | |||||||
1. Linde K, Bemer MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.-
2. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21:703-716.
3. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;31:439-442.
4. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
5. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;(2):CD003390.-
6. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepres-sant. Acta Neurol Scand Suppl. 1994;154:7-14.
7. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression. Clin Invest Med. 2005;28:132-139.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxy-tryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.-
9. Taylor MJ, Wilder H, Bhagwager Z, et al. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;(2):CD004049.-
10. Williams AL, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression? J Affect Disord. 2006;93:117-123.
11. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 longchain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2006;84:1308-1316.
12. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression. BMC Complement Altern Med. 2004;4:12.-
13. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression. Phytother Res. 2005;19:148-151.
14. 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. J Ethnopharmacol. 2005;97:281-284.
15. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression. Phytomedicine. 2006;13:607-611.
16. Sayyah M, Sahhah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:166-169.
17. Schulz V Safety of St. John’s wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13:199-204.
18. Lee S, Gura KM, Kim S, et al. Current clinical applications of ome-ga-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-341.
19. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
ST. JOHN’S WORT is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors) are limited (SOR: A, 1 systematic review).
A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects.
Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety.
N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don’t appear effective in treating major depressive disorder (SOR: A, 1 systematic review.)
Evidence summary
TABLE W1 summarizes study results and recommendations for nutritional therapies for depression.1-16
St. John’s wort works as well as standard antidepressants
A recent Cochrane review suggested that St. John’s wort is more effective than placebo in patients with mild to moderate depression and as effective as standard antidepressants.1
Other supplements also have benefits
A systematic review of 4 small randomized controlled trials (RCTs) suggested that saffron (30 mg) is superior to placebo in treating short-term depression (6 weeks). Treatment and outcomes were equivalent to fluoxetine and imipramine.2 A later RCT yielded results consistent with the systematic review.3
Combined lavender tincture (60 drops per day) and imipramine were more effective than imipramine alone in 1 small RCT.4
Borage, a traditional Persian medicine, was superior to placebo in reducing depressive symptoms in 1 small RCT.2
Dan zhi xiao yao, a traditional Chinese medicine, was as effective as the tricyclic anti-depressant maprotiline in 1 small RCT.2
Three RCTs suggested that folate may be used to supplement conventional treatments for depression, but it isn’t clear whether this would help patients with normal folate levels.5
A meta-analysis of 13 controlled clinical trials and a later systematic review of 11 articles including 2 RCTs concluded that SAMe is more effective than placebo and as efficacious as tricyclic antidepressants in treating major depression in adults. However, further trials are needed to answer questions about absorption, mechanism of action, and bioavailability.6,7
Tryptophan’s benefit comes with risk
In a Cochrane review of 2 RCTs, tryptophan and 5-HTP were superior to placebo in alleviating symptoms of depression. However, some published case reports have linked tryptophan use to potentially fatal eosinophilia-myalgia syndrome.8
No clear evidence for inositol or n-3 PUFAs
A Cochrane review of 4 small double-blind RCTs investigating inositol as a nutritional supplement in depression treatment failed to find clear evidence of therapeutic benefit.9
Three RCTs demonstrated significantly higher red blood cell membrane levels of n-3 PUFAs in nondepressed patients compared with depressed patients.10 However, a systematic review of 12 RCTs failed to demonstrate any benefit of n-3 PUFA supplementation over placebo in treating depressed mood.11 The authors concluded that larger trials are needed to demonstrate efficacy because of marked heterogeneity among the RCTs.
Safety issues. A recent Cochrane review found fewer adverse effects for St. John’s wort than tricyclic antidepressants.1 The most common adverse reactions were sensitivity to light, skin symptoms, gastrointestinal symptoms, and agitation. Data comparing St. John’s wort with newer antidepressants are lacking.
St. John’s wort does have pharmacokinetic interactions and should not be taken concurrently with other antidepressants, immunosuppressants, anti-HIV drugs, cou-marin-type anticoagulants, or certain antineoplastic agents.17
Reviews of meta-analyses, case reports, population studies, RCTs, and other literature have reported virtually no adverse effects for PUFAs; 18 trials investigating saffron, lavender, borage, dan zhi xiao yao, folate, SAMe, and inositol also reported no safety concerns. However, the size and duration of these studies limit their ability to detect significant problems.2,5,6,9 As previously noted, concerns exist regarding an association between tryptophan and eosinophilia-myalgia syndrome.8
Recommendations
The World Federation of Societies of Biological Psychiatry doesn’t recommend St. John’s wort for moderate to severe depression, but suggests it can be considered for treating mild to moderate depressive episodes provided the prescriber considers potential pharmacokinetic interactions with other medications and understands possible variations in purity and potency of extracts.19 The Federation also states that St. John’s wort is an alternative for patients reluctant to take traditional antidepressants.
TABLE W1
What the studies say about nutritional therapies for depression
| Supplement | Study type | Number of subjects | Comparison group | Outcome measure | Results | Conclusion | SOR |
|---|---|---|---|---|---|---|---|
| Borage (Echium amoenum) | 1 small RCT | 352,16 | Placebo | HAM-D | Improved HAM-D scores significantly at week 4 (borage 18. 3±3. 9 vs placebo 21. 9±3. 9; t=2. 51; P=. 02); no significant difference at Week 62,16 | Superior to placebo in reducing symptoms of depression | B |
| Dan zhi xiao yao | 1 small RCT | 632 | Maprotiline | HAM-D, SDS, SAS, scale for traditional Chinese medicine syndrome and symptom differentiation | 87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) | As effective as maprotiline in treating depression | B |
| Folate | Cochrane review of 3 RCTs | 2475 | Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels) | HAM-D | Superior to placebo (NNT=5, defined as 50% reduction in HAM-D); comparable to trazodone (RR=0. 97; 95% CI, 0. 14-2. 01)7 | May have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levels | A |
| Inositol | Cochrane review of 4 RCTs | 1419 | Studies 1-3: placebo plus conventional antidepressants Study 4: placebo only | HAM-D, MADRS | Pooled estimate of effect of all 3 studies (SMD= -0. 08; 95% CI, -0. 45 to 0. 30) | No clear evidence of therapeutic benefit | A |
| Lavender (Lavandula angustifolia) | 1 small RCT | 454 | Imipramine | HAM-D | Imipramine plus lavender showed significant effect compared with imipramine alone (f=26. 87; Df=3. 01; P<. 0001) | Synergistic effect suggested when used with imipramine | B |
| n-3 long-chain polyunsaturated fatty acids | Systematic review including 3 RCTs; 10 meta-analysis of 12 RCTs11 | 10210 103211 | Various comparison groups included | Serum SFAs, MUFAs, PUFAs; RBC membrane levels n-3 PUFAs2 HAM-D, BDI3 | Systematic review:10 Study 1: n=30; ES=3. 61 Study 2: n=24; ES=1. 2 Study 3: n=48; ES=2. 43 Meta-analysis:11 Pooled ES=0. 13; 95% CI, 0. 01-0. 25 | Significantly higher RBC membrane levels of n-3 PUFAs in nondepressed vs depressed patients10 No significant effect for supplementation11 Larger trials with adequate power needed2,3 | A |
| S-adenosyl-methionine (SAMe) | Meta-analysis of 13 RCTs,6 systematic review including 2 RCTs7 | 3996 787 | Placebo and conventional antidepressants | HAM-D | NNT=2. 5 for HAM-D decrease of >25%; 6 NNT=6. 25 for HAM-D decrease of >50%6 | May have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7 | A |
| Saffron (Crocus sativus) | Systematic review of 4 small RCTs, 1 later RCT | 3012 4013 4014 4015 403 | Imipramine12 Placebo13,15 Fluoxetine5,14 | HAM-D | Systematic review: Study 1: imipramine and saffron equally efficacious (f=2. 91; P=. 09)12 Study 2: Improved HAM-D scores: -12. 20±4. 67 (saffron) vs -5. 10±4. 71 (placebo) (P<. 0001)13 Study 3: Improved HAM-D scores: saffron petal -12. 00±4. 10; fluoxetine -13. 50±4. 91; difference between 2 treatments not significant (P=. 27)14 Study 4: Improved HAM-D scores: -14. 01±5. 53 (saffron petal) vs -5. 05±4. 63 (placebo) (P<. 0001)15 Study 5:5 NNT=10 | Efficacy of extract and petal suggested to treat mild to moderate depression Large-scale trials are warranted | B |
| St. John’s wort (Hypericum perforatum L. ) | Cochrane review of 29 RCTs | 54891 | SSRIs, tri/tetracyclic antidepressants, placebo | Responder rate ratio | St. John’s wort vs placebo: 9 larger trials: RR=1. 28; 95% CI, 1. 10-1. 491 9 smaller trials: RR=1. 87; 95% CI, 1. 22-2. 871 St. John’s wort vs SSRIs: 12 trials: RR=1. 00; 95% CI, 0. 90-1. 111 St. John’s wort vs tricyclics: 5 trials: RR=1. 02; 95% CI, 0. 90-1. 151 | Effective for treating mild to moderate depression | A |
| Tryptophan and 5-hydroxy-tryptophan (5-HTP) | Cochrane review of 2 RCTs | 648 | Placebo | HAM-D | NNT=2. 78 vs placebo (OR=4. 1; 95% CI, 1. 28-13. 15 | Superior to placebo Insufficient evidence regarding safety | A |
| BDI, Beck Depression Inventory; CI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; HAM-D, Hamilton Depression Rating Scale; MADRS, Mont-gomery-Asberg Depression Rating Scale; MUFAs, monounsaturated fatty acids; n-3 PUFAs, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; OR, odds ratio; PUFAs, polyunsaturated fatty acids; RBC, red blood cell; RCT, randomized controlled trial; RR, relative risk; SAS, self-rating anxiety scale; SDS, self-rating depression scale; SFAs, saturated fatty acids; SMD, standard weighted mean difference; SOR, strength of recommendation; SSRI, selective serotonin reuptake inhibitor. | |||||||
ST. JOHN’S WORT is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors) are limited (SOR: A, 1 systematic review).
A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects.
Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety.
N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don’t appear effective in treating major depressive disorder (SOR: A, 1 systematic review.)
Evidence summary
TABLE W1 summarizes study results and recommendations for nutritional therapies for depression.1-16
St. John’s wort works as well as standard antidepressants
A recent Cochrane review suggested that St. John’s wort is more effective than placebo in patients with mild to moderate depression and as effective as standard antidepressants.1
Other supplements also have benefits
A systematic review of 4 small randomized controlled trials (RCTs) suggested that saffron (30 mg) is superior to placebo in treating short-term depression (6 weeks). Treatment and outcomes were equivalent to fluoxetine and imipramine.2 A later RCT yielded results consistent with the systematic review.3
Combined lavender tincture (60 drops per day) and imipramine were more effective than imipramine alone in 1 small RCT.4
Borage, a traditional Persian medicine, was superior to placebo in reducing depressive symptoms in 1 small RCT.2
Dan zhi xiao yao, a traditional Chinese medicine, was as effective as the tricyclic anti-depressant maprotiline in 1 small RCT.2
Three RCTs suggested that folate may be used to supplement conventional treatments for depression, but it isn’t clear whether this would help patients with normal folate levels.5
A meta-analysis of 13 controlled clinical trials and a later systematic review of 11 articles including 2 RCTs concluded that SAMe is more effective than placebo and as efficacious as tricyclic antidepressants in treating major depression in adults. However, further trials are needed to answer questions about absorption, mechanism of action, and bioavailability.6,7
Tryptophan’s benefit comes with risk
In a Cochrane review of 2 RCTs, tryptophan and 5-HTP were superior to placebo in alleviating symptoms of depression. However, some published case reports have linked tryptophan use to potentially fatal eosinophilia-myalgia syndrome.8
No clear evidence for inositol or n-3 PUFAs
A Cochrane review of 4 small double-blind RCTs investigating inositol as a nutritional supplement in depression treatment failed to find clear evidence of therapeutic benefit.9
Three RCTs demonstrated significantly higher red blood cell membrane levels of n-3 PUFAs in nondepressed patients compared with depressed patients.10 However, a systematic review of 12 RCTs failed to demonstrate any benefit of n-3 PUFA supplementation over placebo in treating depressed mood.11 The authors concluded that larger trials are needed to demonstrate efficacy because of marked heterogeneity among the RCTs.
Safety issues. A recent Cochrane review found fewer adverse effects for St. John’s wort than tricyclic antidepressants.1 The most common adverse reactions were sensitivity to light, skin symptoms, gastrointestinal symptoms, and agitation. Data comparing St. John’s wort with newer antidepressants are lacking.
St. John’s wort does have pharmacokinetic interactions and should not be taken concurrently with other antidepressants, immunosuppressants, anti-HIV drugs, cou-marin-type anticoagulants, or certain antineoplastic agents.17
Reviews of meta-analyses, case reports, population studies, RCTs, and other literature have reported virtually no adverse effects for PUFAs; 18 trials investigating saffron, lavender, borage, dan zhi xiao yao, folate, SAMe, and inositol also reported no safety concerns. However, the size and duration of these studies limit their ability to detect significant problems.2,5,6,9 As previously noted, concerns exist regarding an association between tryptophan and eosinophilia-myalgia syndrome.8
Recommendations
The World Federation of Societies of Biological Psychiatry doesn’t recommend St. John’s wort for moderate to severe depression, but suggests it can be considered for treating mild to moderate depressive episodes provided the prescriber considers potential pharmacokinetic interactions with other medications and understands possible variations in purity and potency of extracts.19 The Federation also states that St. John’s wort is an alternative for patients reluctant to take traditional antidepressants.
TABLE W1
What the studies say about nutritional therapies for depression
| Supplement | Study type | Number of subjects | Comparison group | Outcome measure | Results | Conclusion | SOR |
|---|---|---|---|---|---|---|---|
| Borage (Echium amoenum) | 1 small RCT | 352,16 | Placebo | HAM-D | Improved HAM-D scores significantly at week 4 (borage 18. 3±3. 9 vs placebo 21. 9±3. 9; t=2. 51; P=. 02); no significant difference at Week 62,16 | Superior to placebo in reducing symptoms of depression | B |
| Dan zhi xiao yao | 1 small RCT | 632 | Maprotiline | HAM-D, SDS, SAS, scale for traditional Chinese medicine syndrome and symptom differentiation | 87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) | As effective as maprotiline in treating depression | B |
| Folate | Cochrane review of 3 RCTs | 2475 | Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels) | HAM-D | Superior to placebo (NNT=5, defined as 50% reduction in HAM-D); comparable to trazodone (RR=0. 97; 95% CI, 0. 14-2. 01)7 | May have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levels | A |
| Inositol | Cochrane review of 4 RCTs | 1419 | Studies 1-3: placebo plus conventional antidepressants Study 4: placebo only | HAM-D, MADRS | Pooled estimate of effect of all 3 studies (SMD= -0. 08; 95% CI, -0. 45 to 0. 30) | No clear evidence of therapeutic benefit | A |
| Lavender (Lavandula angustifolia) | 1 small RCT | 454 | Imipramine | HAM-D | Imipramine plus lavender showed significant effect compared with imipramine alone (f=26. 87; Df=3. 01; P<. 0001) | Synergistic effect suggested when used with imipramine | B |
| n-3 long-chain polyunsaturated fatty acids | Systematic review including 3 RCTs; 10 meta-analysis of 12 RCTs11 | 10210 103211 | Various comparison groups included | Serum SFAs, MUFAs, PUFAs; RBC membrane levels n-3 PUFAs2 HAM-D, BDI3 | Systematic review:10 Study 1: n=30; ES=3. 61 Study 2: n=24; ES=1. 2 Study 3: n=48; ES=2. 43 Meta-analysis:11 Pooled ES=0. 13; 95% CI, 0. 01-0. 25 | Significantly higher RBC membrane levels of n-3 PUFAs in nondepressed vs depressed patients10 No significant effect for supplementation11 Larger trials with adequate power needed2,3 | A |
| S-adenosyl-methionine (SAMe) | Meta-analysis of 13 RCTs,6 systematic review including 2 RCTs7 | 3996 787 | Placebo and conventional antidepressants | HAM-D | NNT=2. 5 for HAM-D decrease of >25%; 6 NNT=6. 25 for HAM-D decrease of >50%6 | May have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7 | A |
| Saffron (Crocus sativus) | Systematic review of 4 small RCTs, 1 later RCT | 3012 4013 4014 4015 403 | Imipramine12 Placebo13,15 Fluoxetine5,14 | HAM-D | Systematic review: Study 1: imipramine and saffron equally efficacious (f=2. 91; P=. 09)12 Study 2: Improved HAM-D scores: -12. 20±4. 67 (saffron) vs -5. 10±4. 71 (placebo) (P<. 0001)13 Study 3: Improved HAM-D scores: saffron petal -12. 00±4. 10; fluoxetine -13. 50±4. 91; difference between 2 treatments not significant (P=. 27)14 Study 4: Improved HAM-D scores: -14. 01±5. 53 (saffron petal) vs -5. 05±4. 63 (placebo) (P<. 0001)15 Study 5:5 NNT=10 | Efficacy of extract and petal suggested to treat mild to moderate depression Large-scale trials are warranted | B |
| St. John’s wort (Hypericum perforatum L. ) | Cochrane review of 29 RCTs | 54891 | SSRIs, tri/tetracyclic antidepressants, placebo | Responder rate ratio | St. John’s wort vs placebo: 9 larger trials: RR=1. 28; 95% CI, 1. 10-1. 491 9 smaller trials: RR=1. 87; 95% CI, 1. 22-2. 871 St. John’s wort vs SSRIs: 12 trials: RR=1. 00; 95% CI, 0. 90-1. 111 St. John’s wort vs tricyclics: 5 trials: RR=1. 02; 95% CI, 0. 90-1. 151 | Effective for treating mild to moderate depression | A |
| Tryptophan and 5-hydroxy-tryptophan (5-HTP) | Cochrane review of 2 RCTs | 648 | Placebo | HAM-D | NNT=2. 78 vs placebo (OR=4. 1; 95% CI, 1. 28-13. 15 | Superior to placebo Insufficient evidence regarding safety | A |
| BDI, Beck Depression Inventory; CI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; HAM-D, Hamilton Depression Rating Scale; MADRS, Mont-gomery-Asberg Depression Rating Scale; MUFAs, monounsaturated fatty acids; n-3 PUFAs, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; OR, odds ratio; PUFAs, polyunsaturated fatty acids; RBC, red blood cell; RCT, randomized controlled trial; RR, relative risk; SAS, self-rating anxiety scale; SDS, self-rating depression scale; SFAs, saturated fatty acids; SMD, standard weighted mean difference; SOR, strength of recommendation; SSRI, selective serotonin reuptake inhibitor. | |||||||
1. Linde K, Bemer MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.-
2. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21:703-716.
3. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;31:439-442.
4. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
5. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;(2):CD003390.-
6. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepres-sant. Acta Neurol Scand Suppl. 1994;154:7-14.
7. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression. Clin Invest Med. 2005;28:132-139.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxy-tryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.-
9. Taylor MJ, Wilder H, Bhagwager Z, et al. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;(2):CD004049.-
10. Williams AL, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression? J Affect Disord. 2006;93:117-123.
11. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 longchain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2006;84:1308-1316.
12. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression. BMC Complement Altern Med. 2004;4:12.-
13. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression. Phytother Res. 2005;19:148-151.
14. 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. J Ethnopharmacol. 2005;97:281-284.
15. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression. Phytomedicine. 2006;13:607-611.
16. Sayyah M, Sahhah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:166-169.
17. Schulz V Safety of St. John’s wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13:199-204.
18. Lee S, Gura KM, Kim S, et al. Current clinical applications of ome-ga-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-341.
19. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
1. Linde K, Bemer MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.-
2. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21:703-716.
3. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;31:439-442.
4. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
5. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;(2):CD003390.-
6. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepres-sant. Acta Neurol Scand Suppl. 1994;154:7-14.
7. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression. Clin Invest Med. 2005;28:132-139.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxy-tryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.-
9. Taylor MJ, Wilder H, Bhagwager Z, et al. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;(2):CD004049.-
10. Williams AL, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression? J Affect Disord. 2006;93:117-123.
11. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 longchain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2006;84:1308-1316.
12. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression. BMC Complement Altern Med. 2004;4:12.-
13. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression. Phytother Res. 2005;19:148-151.
14. 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. J Ethnopharmacol. 2005;97:281-284.
15. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression. Phytomedicine. 2006;13:607-611.
16. Sayyah M, Sahhah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:166-169.
17. Schulz V Safety of St. John’s wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13:199-204.
18. Lee S, Gura KM, Kim S, et al. Current clinical applications of ome-ga-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-341.
19. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
Evidence-based answers from the Family Physicians Inquiries Network