Since the development of Prozac, the first of the selective serotonin-reuptake inhibitors (SSRIs), this family of drugs has been expanding. The SSRIs are used for both severe and mild to moderate depression as well as for a variety of other conditions. These drugs work primarily by altering the action of the neurotransmitter (chemical messenger) serotonin in the brain. SSRI antidepressants include
Other antidepressants that increase serotonin activity include
Possible Harmful Interaction
The body uses the natural substance 5-hydroxytryptophan (5-HTP) to manufacture serotonin, and supplemental forms have been used for treating depression and migraine headaches.
S-adenosylmethionine (SAMe) is a naturally occurring compound derived from the amino acid methionine and the energy molecule adenosine triphosphate (ATP). SAMe is widely used as a supplement for treating osteoarthritis and depression.
Based on one case report and current thinking about how they work, SAMe and 5-HTP should not be taken with SSRIs, as they might increase the risk of serotonin syndrome.
This syndrome is a toxic reaction brought on by too much serotonin activity. The condition requires immediate medical attention, with symptoms including anxiety, restlessness, confusion, weakness, tremor, muscle twitching or spasm, high fever, profuse sweating, and rapid heartbeat.
Although SAMe is not currently known to affect serotonin, it does appear to have antidepressant effects and may in some way increase serotonin activity.
Because SSRIs increase serotonin activity even more than clomipramine, a similar problem might occur if you combine SAMe with an SSRI.
The supplement 5-HTP is used by the body to manufacture serotonin, so it could also increase the risk of serotonin syndrome when combined with an SSRI.
Possible Harmful Interaction
The herb St. John's wort (Hypericum perforatum) is primarily used to treat mild to moderate depression. One of its actions appears to be increasing the activity of serotonin in the brain.
If you are taking an SSRI medication, do not take the herb St. John's wort at the same time. It is possible that your serotonin levels might be raised too high, causing a dangerous condition called serotonin syndrome.2,3 (Please see previous topic.)
Several case reports appear to bear this out. Serotonin syndrome was reported in five elderly individuals who began using St. John's wort while taking sertraline (four reports) or nefazodone (one report).4 One individual had symptoms resembling serotonin syndrome after combining paroxetine (50 mg daily) and St. John's wort (600 mg daily).5 Another person taking St. John's wort with two other serotonin-enhancing drugs was reported to experience serotonin syndrome.6
Furthermore, if you wish to switch from an SSRI to St. John's wort, you may need to wait a few weeks for the SSRI to wash out of your system before it is safe to start taking the herb. The waiting time required depends on which SSRI you are taking. Ask your physician or pharmacist for advice.
Possible Helpful Interaction
Folate is a B vitamin that offers many important health benefits. Not only does it help prevent birth defects and possibly reduce the risk of heart disease, a recent study suggests that folate can also help SSRI antidepressants work better.
In this double-blind, placebo-controlled trial, 127 individuals with severe depression were given either Prozac plus folate (500 mcg daily) or Prozac alone.10 Researchers wanted to see whether the vitamin would increase the medication's effectiveness.
The results were different for men and women. Female participants definitely benefited from receiving folate along with the medication. While just under 50% of the women taking Prozac alone fully recovered from their depression, combination treatment produced a recovery rate of nearly 75%. This is a very marked difference, and one that makes a strong case for combining folate with antidepressant therapy.
Men, however, did not do any better on combination treatment than on Prozac alone. Researchers found evidence that a higher dose would have been necessary for male participants, perhaps 800 to 1,000 mcg daily. However, for dosages this high, medical supervision is necessary.
Supplementation Probably Not Helpful
Fish oil contains essential fatty acids in the omega-3 family. Fish oil, its constituents, and a slightly modified fish oil constituent called ethyl-EPA have all been tested for treatment of depression. While a few small studies have suggested that these substances might enhance the effectiveness of antidepressant drugs;25-28 the results of larger and better designed studies have been mostly negative.14-24
Supplementation Probably Not Helpful
SSRIs can cause many sexual side effects, including inability to achieve orgasm (in women) and impotence (in men). Case reports and open studies raised hopes that the herb ginkgo could help reverse these problems.7-9 However, only double-blind, placebo-controlled studies can truly establish efficacy of a treatment, and when studies of this type were finally performed to evaluate ginkgo's potential effectiveness for this purpose, no benefits were seen.11-12
Supplementation probably not helpful
As with ginkgo, ephedrine (extracted from the herb ephedra) does not appear any more effective than placebo for treatment of female sexual dysfunction caused by SSRIs.
1. Iruela LM, Minguex L, Merino J, et al. Toxic interaction of S-adenosylmethionine and clomipramine [letter]. Am J Psychiatry. 1993;150:522.
2. Demott K. St. John's wort tied to serotonin syndrome. Clin Psychiatry News. 1998;26:28.
3. Gordon JB. SSRIs and St. John's wort: possible toxicity? [letter]. Am Fam Physician. 1998;57:950, 953.
4. Lantz MS, Buchalter E, Giambanco V. St. John's wort and antidepressant drug interactions in the elderly. J Geriatr Psychiatry Neurol. 1999;12:7-10.
5. Gordon JB. SSRIs and St. John's wort: possible toxicity? [letter]. Am Fam Physician. 1998;57:950,953.
6. Demott K. St. John's wort tied to serotonin syndrome. Clin Psychiatry News. 1998;26:28.
7. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24:139-143.
8. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998;24:139-143.
9. McCann B. Botanical could improve sex lives of patients on SSRIs. Drug Topics. 1997;141:33.
10. 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.
11. Kang BH, Lee SJ, Kim MD, et al. A placebo-controlled, double-blind trial of Ginkgo bilboa for antidepressant-induced sexual dysfunction. Hum Psychopharmacol Clin Exp. 2002;17:279-84.
12. Wheatley D. Triple-blind, placebo-controlled trial of Ginkgo biloba in sexual dysfunction due to antidepressant drugs. Hum Psychopharmacol. 2004 Sep 20 [Epub ahead of print].
13. Meston CM. A Randomized, Placebo-Controlled, Crossover Study of Ephedrine for SSRI-Induced Female Sexual Dysfunction. J Sex Marital Ther. 2004;30:57-68.
14. 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.
15. 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.
16. 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.
17. 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.
18. Peet M. Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results. Prostaglandins Leukot Essent Fatty Acids. 2003;69:477-485.
19. 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.
20. 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.
21. 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.
22. 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]
23. 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.
24. 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]
25. 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.
26. 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.
27. Peet M. Eicosapentaenoic acid in the treatment of schizophrenia and depression: rationale and preliminary double-blind clinical trial results. Prostaglandins Leukot Essent Fatty Acids. 2003;69:477-485.
28. 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;42:192-8.
Last reviewed August 2013 by EBSCO CAM Review Board
Last Updated: 8/22/2013
EBSCO Information Services is fully accredited by URAC. URAC is an independent, nonprofit health care accrediting organization dedicated to promoting health care quality through accreditation, certification and commendation.
This content is reviewed regularly and is updated when new and relevant evidence is made available. This information is neither intended nor implied to be a substitute for professional medical advice. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with questions regarding a medical condition.
To send comments or feedback to our Editorial Team regarding the content please email us at firstname.lastname@example.org. Our Health Library Support team will respond to your email request within 2 business days.