An Important Lesson From Mr. T
Recently, I was evaluating a patient, Mr. T., who has been suffering with severe Obsessive Compulsive Disorder and Depression for many years. Mr. T. had been experiencing increased irritability, insomnia, sweating, diarrhea, and tremulousness for many weeks. He presented to my office on escitalopram (Lexapro) 40mg daily, trazodone (Desyrel) 50mg nightly, gabapentin (Neurontin) 1,200mg daily as needed for anxiety, and lorazepam (Ativan) 4mg per day as needed for anxiety. Toward the end of the interview, I asked him about any alternative treatments he may be using and was horrified when he provided the list of supplements he was taking:
Cobalamin (Vitamin B12)
Mr. T reported that he had been seeing a “Naturopathic doctor” who specializes in “Integrative Medicine.” He was also being treated by a Psychiatrist. Concerned about mild serotonin toxicity, I recommended he stop the supplements. Although ambivalent about stopping his supplements, his symptoms of irritability, insomnia, sweating, diarrhea, and tremulousness gradually improved over the course of a few weeks.
An Unregulated Industry
Herbs and supplements may be beneficial in some patients, but the most important thing to know about the supplement industry in the United States is that supplements are not regulated by the Food and Drug Administration (FDA). Normally, novel treatments go through an extensive review process by the FDA before they are brought to market. That is, novel treatments require appropriately designed clinical trials demonstrating safety and efficacy before they are approved.
The FDA also regulates the manufacturing and testing of medications to be sure contaminants are removed and the active ingredient is, in fact, present at the dose indicated on the label. Unfortunately, this is not the case with many supplements and herbs, and this means you might not be getting what you paid for. That being said, there are third-party laboratories that test supplements for potency and accuracy. Therefore, at minimum, be sure to check that the supplement you buy has been tested or is from a reputable company.
Omega-3 Fatty Acids
Omega-3 and Omega-6 fatty acids are building blocks for lipids or fats in our bodies. The omega-3 long-chain fatty acids include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
Fatty acids are essential components of the membranes of our cells and are precursors to many hormones and signaling molecules in our cells. Some studies have suggested lower omega-3 fatty acids in the membranes of red blood cells of depressed patients compared with nondepressed controls.
A 2008 Cochrane review of five trials of omega-3 fatty acids as an add-on treatment for bipolar disorder found that these supplements are unlikely to help with manic symptoms but might help depressive symptoms (Montgomery and Richardson 2008). A 2014 meta-analysis of supplemental Omega-3 fatty acids in depression also suggested a trend toward alleviating depressive symptoms (Grosso et al 2014).
The risks associated with omega 3 are relatively low and therefore I sometimes recommend the addition of Omega-3 supplementation at a dose of 1 gram of EPA/DHA per day (with at least 60% EPA) or the addition of one to two servings of a fatty fish, such as salmon, per week. Omega-3 fatty acids have anticoagulant properties and therefore may increase the risk of bleeding in some patients who take “blood thinners” or have pre-existing bleeding problems.
Omega-3 monotherapy is not a recommended first line treatment for depression and is not something I routinely recommend. To date, there is growing support but still insufficient evidence for omega-3 monotherapy in patients suffering from depression, especially those suffering with more severe depression.
St. John’s Wort
Hypericum perforatum, or St. John’s Wort, is a flowering plant native to Europe and Asia and has been used in ancient medicine practices. The active ingredients in St. John’s Wort are the phytochemicals hyperforin and hypericin.
While there is some evidence from controlled studies supporting St John’s Wort for mild to moderate depression, the data is not convincing and limited by low sample size and inconsistent diagnostic criteria. A study in JAMA found it no more effective than placebo or sertraline for moderate to severe depression.
In my opinion, St. John’s Wort has the potential to cause more harm than benefit. St John’s Wort interacts with many medications such as traditional antidepressants, birth control pills, medications for HIV/AIDs, and warfarin to name a few.
Combining serotonergic antidepressants with St John’s Wort significantly increases the risk of serotonin toxicity (i.e. serotonin syndrome), a potentially life threatening condition. If used, doses ranging from 300mg-900mg per day in divided doses have been reported as effective and safe but further studies are warranted.
5-hydroxytryptophan (5HTP) is derived from the amino acid L-Tryptophan and is the immediate precursor in the synthesis of the neurotransmitter serotonin, also known as 5-hydroxytryptamine (5HT). 5HTP is not found in our diet and requires specific enzymes in our body to be produced from L-Tryptophan, which is a dietary amino acid.
The theoretical rationale for using 5HTP as a supplement is to boost serotonin levels in the brain. If only our understanding of the neurochemistry of depression and anxiety were that simple, it would make sense. But depression isn’t just about serotonin or other monoamines.
Furthermore, the dearth of adequately powered studies and the overall lack of supporting evidence is important to consider. Currently, we do not have appropriate safety data about dosing or drug-drug interactions to be confident using 5HTP for any psychiatric disorder. In fact, combining 5HTP with serotonergic antidepressants or with medications used in Parkinson’s Disease, may increase the risk of serotonin toxicity and hypertensive emergencies, both of which can be life-threatening.
Folate, or folic acid, is a B vitamin that is vital for appropriate neurological functioning. Through a series of biochemical transformations, Folic acid is converted to dihydrofolate, tetrahydrofolate, and L-methylfolate. L-methylfolate is an important regulator in the production of monoamines such as serotonin, norepinephrine, and dopamine.
Low levels of L-methylfolate, either from dietary deficiency or from genetics, may result in lower levels of these monoamines in the brain. This is important because classic antidepressants will only work to “boost” serotonin, norepinephrine, and dopamine if there is enough of these monoamines being produced to begin with. Therefore, addition of L-methylfolate may be beneficial in patients who are not responding to classic antidepressants or who have a specific genetic variant for methylene tetrahydrofolate reductase (MTHFR), an important enzyme in the production L-methylfolate.
There is no consensus as to what dose of L-methylfolate is best, but doses between 7.5mg-15mg daily are considered safe in most patients. It is important to note that supplementation of folate or methylfolate may mask vitamin B12 deficiency. Therefore, B12 levels should be obtained prior to supplementing with folate or methylfolate.
Of the many different supplements, S-adenosylmethionine (SAMe) is one with relatively more evidence supporting its use in depression. The antidepressant mechanism of SAMe is still unclear but may have to do with “silencing” certain genes that are involved in the breakdown of monoamines like serotonin, dopamine, and norepinephrine. By “silencing” these genes, the levels of serotonin, dopamine, and norepinephrine can be theoretically enhanced.
Genes can be “silenced” by adding a methyl group via a biochemical reaction called methylation. SAMe plays a major role in methylation reactions in our body and is derived from methionine, which is itself derived from L-methylfolate.
The addition of SAMe at doses ranging from 800mg-1600mg/day is most appropriate in patients who do not respond or partially respond to classic antidepressant therapy. A major concern with SAMe is the accumulation of its undesirable metabolite homocysteine which has been associated with heart attacks, strokes, and other serious medical conditions.
Physicians are scientists. We use scientific data to support our clinical decisions. That being said, the “off-label” use of medications, supplements, and herbs based on anecdotal evidence is common practice and can be beneficial to many patients but only when these treatments are used judiciously under the supervision of a medical professional who understands the pathophysiological and pharmacological mechanisms involved in the ailment(s) being treated.
- Grosso G, Pajak A, Marventano S, et al: Role of Omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials. 2014.
- Montgomery P, Richardson AJ: Omega 3 fatty acids for bipolar disorder. Cochrane Database Systematic Review. 2008
- Papakostas GI, Mischoulon D, Shyu I et al. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. 2010.
- Papakostas GI. The role of S-adenosyl methionine in the treatment of depression. 2009.
- Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
- Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
- Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
- Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
- Stein, Lerer, and Stahl. Essential Evidence-Based Psychopharmacology. Second Edition. 2012.
- Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
- Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.