The medical literature generally supports the use of SAMe in doses of 400-1,600 mg/day. “It’s generally well tolerated.” Dr. Mischoulon said. Side effects tend to resemble the usual ones clinicians see with antidepressants: insomnia, anorexia, constipation, nausea, dry mouth, sweating, dizziness, and anxiety. “There have been cases of mania or hypomania developing in patients with bipolar depression, so be careful about [using this] in people with bipolar disorder,” he said.
Pregnancy tends to decrease methylation and SAMe activity, “so theoretically it should be beneficial in pregnant women with intrahepatic cholestasis, but we have limited prospective safety data on SAMe in pregnant women, so we advise caution.”
Cost may be a barrier for some patients, he said, since a 400-mg tablet may cost as much as $1.25. “So if you’re one of those people who need a dose in the range of 2,000-3,000 mg, the costs can be quite significant. Discuss this with your patient before you decide to embark on a trial of SAMe.”
• L-methylfolate (Deplin). Dr. Mischoulon was part of a multicenter research team that carried out a study of L-methylfolate 15 mg/day versus placebo in 223 adult patients with SSRI-resistant major depressive disorder (Am J Psychiatry. 2010 Aug;167[8]:942-8). They conducted the study in two 30-day treatment phases using a sequential parallel comparator design, and found that the mean change from baseline on the Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR) was significantly greater with L-methylfolate, compared with placebo. Similar results were observed with the HDRS-17, the HDRS-28, and the Clinical Global Impression–Severity scale (CGI-S).
• Omega-3 fatty acids (DHA and EPA). Primarily found in fish oil and other marine sources, omega-3 fatty acids are believed to promote neuronal membrane stabilization and anti-inflammatory effects. To date, more than 30 randomized, controlled trials of fatty acids for the treatment of depression have been conducted, mostly omega-3 fatty acids as an adjunct to standard antidepressant therapy. Most of the studies have involved EPA by itself or EPA in combination with DHA, he said, at a dose of 1-2 g per day. There’s also evidence that EPA may have a role in prophylactic preinterferon therapy in patients with hepatitis C.
Dr. Mischoulon and his associates recently carried out a trial of EPA 1,000 mg/day or DHA 1,000 mg/day, or placebo for 8 weeks in 196 patients (J Clin Psychiatry. 2015;76[1]:54-61). All treatment arms showed improvement, but neither treatment outperformed placebo. Response rates were in the range of 40%-50% for each arm, and the remission rates were in the 30% range. Though the initial results “were discouraging,” a secondary analysis revealed that EPA may benefit individuals with abnormal levels of two or more of the following inflammatory biomarkers at baseline: human C-reactive protein, interleukin-6, interleukin-1 receptor antagonist, leptin, and adiponectin. A new study underway “will examine depressed patients with obesity and elevated inflammatory status at baseline to enhance signal detection,” he said.
For the time being, he said, it’s best to use omega-3 fatty acids in patients with unipolar depression, in a dose of 1-2 g/day of an EPA/DHA combination that contains at least 60% EPA. In patients with bipolar disorder, he uses doses in the range of 6-10 g/day, “but watch out for cycling, which is a common problem in people with bipolar illness.”
Side effects from use may include stomach upset and fishy taste, “although most preparations today are highly purified, so we tend to get fewer complaints about that.” Published studies suggest a benefit of omega-3 fatty acids to expectant mothers, the fetus, and infants, particularly for neural development, “but the safe upper limit in pregnancy is unknown, so we need to advise caution.”
Dr. Mischoulon reported that he has received research support from the Bowman Family Foundation, Fisher Wallace, Nordic Naturals, Methylation Sciences, and PharmoRx Therapeutics. He also has received honoraria for consulting, speaking, and writing from Pamlab and the Massachusetts General Hospital Psychiatry Academy.