LAS VEGAS (FRONTLINE MEDICAL NEWS) In the clinical opinion of Dr. David Mischoulon, certain complementary and alternative medicine therapies such as St. John’s wort and omega-3 fatty acids may benefit some patients with mild to moderate depression.

At the annual psychopharmacology update held by the Nevada Psychiatric Association, Dr. Mischoulon said more than 70% of people worldwide have used some form of complementary therapy at some point in their lives.

“They often don’t have as many severe side effects as synthetic medication,” he said. “However, the body of knowledge about these therapies is limited. We don’t have as much systematic research or rigorous clinical trials of these treatments, so as clinicians who are put in the position of making recommendations, we don’t know how effective these treatments are compared to placebo or standard therapies.”

Then there’s the common public misconception that just because something is “natural” or can be bought over the counter, it’s automatically safe. “That isn’t the case,” said Dr. Mischoulon, director of research for the Depression Clinical & Research Program at Massachusetts General Hospital, Boston. “There have been a number of cases of adverse reactions when these natural products are taken along with standard medications. Another problem is that these products have different manufacturers that may use different techniques for preparing them, so the purity may vary. Also, most of these natural therapies are not covered by health insurance.”

He highlighted the following natural agents that are used to treat depression:

• St. John’s wort. He described this as “probably the most popular herbal remedy for depression,” with about 40 published trials to date: 26 placebo controlled, and 14 with standard antidepressant comparators. Studies have been limited by short duration, he said, and appear to favor its use for mild to moderate depression. Hypericin, hyperforin, and adhyperforin contained in St. John’s wort are thought to be the key ingredients.

“It’s thought that they might interact with cytokine production through the [hypothalamic-pituitary-adrenal] axis,” Dr. Mischoulon explained. “Consequently, this interaction could result in decreased cortisol production, which may attenuate depression.”

Side effects from using St. John’s wort are similar to those found with antidepressants, including dry mouth, dizziness, and constipation. “It’s generally thought to be safe,” he said. Phototoxicity can be an issue for some, and using St. John’s wort with selective serotonin reuptake inhibitors is not advised because of the potential for developing serotonin syndrome. Several cases of colic, drowsiness, and lethargy have been reported in breastfed infants whose mothers were taking St. John’s wort, and low birth weight from in utero exposure has been demonstrated in animal studies.

Dr. Mischoulon noted that St. John’s wort induces CYP3A4 expression, which reduces the therapeutic activity of numerous drugs, including warfarin, cyclosporine, oral contraceptives, digoxin, zolpidem, and olanzapine. Caution is required in HIV-positive, cancer, and organ transplant patients. “Overall the results for St. John’s wort as reported in the literature are encouraging but with some inconsistencies,” he said. “The best individuals for St. John’s wort are individuals with mild to moderate depression, and less so individuals with more severe depression.” He recommends a dose of 900-1,200 mg per day, “but do remember that different preparations of St. John’s wort may vary in potency, so in some cases you may need to go to a higher dose.”

• S-adenosylmethionine (SAMe). Present in all living beings, this substance is required for neurotransmitter synthesis, and depends on folate and B12 levels to function optimally. According to Dr. Mischoulon, SAMe has been evaluated in more than 45 randomized clinical trials involving various routes of administration in doses of 200-1,600 mg/day. In eight placebo-controlled studies, SAMe was superior to placebo in six trials and had similar efficacy in the other two. In eight studies that compared SAMe with tricyclic antidepressants, six demonstrated similar efficacy with TCAs and one demonstrated benefit of SAMe over imipramine. The other trial, led by Dr. Mischoulon, compared SAMe with escitalopram and placebo in 189 patients in three treatment arms over a course of 12 weeks ( J Clin Psychiatry. 2014;75[4]:370-6 ). The researchers observed a benefit in all treatment arms (a drop of 5-6 points on the 17-item Hamilton Depression Rating Scale [HDRS-17]), but no statistically significant differences were found between the groups. The most common side effect in the SAMe arm was related to gastrointestinal issues, mainly stomach discomfort and diarrhea.

One of the appeals of SAMe is that it’s safe to use in combination with other medicines, including tricyclic antidepressants (TCAs). “It may even boost and accelerate the effect of TCAs,” Dr. Mischoulon said. “It’s also been combined successfully with SSRIs and” [selective serotonin norepinephrine inhibitors]. In one study of 30 patients who were partial or nonresponders to SSRIs, augmentation with SAMe led to a response rate of 50% and a remission rate of 43% at 6 weeks ( J Clin Psychopharmacol. 2004;24[6]:661-4 ), “which is very encouraging for our treatment-resistant population,” he said. In a 2010 trial, researchers investigated augmentation with SAMe 800 mg b.i.d. or placebo for 6 weeks in 73 serotonin reuptake inhibitor nonresponders with major depressive disorder ( Am J Psychiatry 2010;167[8]:942-8 ). The response rate was 36.1% in the SAMe group, compared with 17.6% in the placebo group.

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.


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