[Transcript edited for clarity]

Hello, and welcome to the Carlat Psychiatry webinar, where we're going to talk S-adenosylmethionine (SAMe) in clinical practice. 

Learning Objectives

After taking this webinar, clinicians should be able to:

1. Understand how to use SAMe in clinical practice

2. Demonstrate an understanding of mechanisms of action

3. Outline uses for SAMe use in depression and in medical illness 

4. Communicate with patients the risks and side effects

Hello everyone. And welcome to the Carlat Psychiatry webinar series. My name is Dr. Garrett Rossi. I'm going to be taking you through today's webinar and we're going to be discussing a topic that I think will be of great interest to you, and that is using S-adenosylmethionine or SAMe in clinical practice.

I'm an adult psychiatrist. I work at Atlanticare Regional Medical Center in the inpatient unit. I have no conflicts of interest to disclose. 

Today we're going to be covering a lot, and I’m going to hit the following key learning objectives for you in this webinar.

At the end of this presentation, clinicians should be able to number one, understand how to use SAMe in clinical practice. Two, we're hoping that you can demonstrate an understanding of the mechanism of action of SAMe. When we're offering this medication and this treatment to our patients, we understand why it works and why it’s potentially a good option for patients suffering from depression. Three, we want to outline the uses of SAMe in depression and depression associated with medical illnesses. I'm going to go over each one of those in detail and indicate why SAMe is useful for the treatment of depression. Four, we're going to communicate with our patients, the risks and side effects of using SAMe

I don't know about you, but majority of the patients that I encounter in clinical practice already use some form of complimentary alternative medicine (CAM). That might be a dietary supplement, vitamin mineral supplement, but the point is, many of them are already using some form of CAM. This is influenced in part because there's no shortage of people promoting the health benefits, both physical and mental health of various dietary supplements. If you're like me, you're skeptical of the use of these products because they usually lack the appropriate clinical trials to support the claims made by the manufactures. 

Hopefully today, I'm going to change your mind about that.

Complimentary alternative medicine is being used all the time by our patients. The use of complimentary alternative medicine in the United States among adults is 38%. What was more surprising is 12% of children were using some form of CAM therapy. 

The challenge for us as clinicians is most CAM treatments are poorly researched. There's a lack of substantial evidence in the literature to support their use. Dietary supplement manufacturing is poorly controlled and not regulated by the FDA. What's written on the label is not always what's in the product. Purity and potency is not standardized across manufacturers, and it makes it difficult for us as clinicians to appropriately advise the patient on which product to take. There are some ways around that. A very resourceful website to have access to is ConsumerLab.com. I would encourage you to check it out if you have patients who are taking any CAM. ConsumerLab is an online resource that tests for the purity and potency of various CAM products on the market. The site provides reviews of these products and they help us to make informed decisions about which ones to recommend to our patients. 

That brings us to one of the more important points that I want to stress for you guys here, and that is how does SAMe work? It's important to know the mechanism of action. Often in psychiatry, the mechanisms are not well teased out. It's theoretical in some cases, but here we have some pretty good evidence to support the mechanism of action.

SAMe has multiple mechanisms of action (MOA) that may contribute to its benefit in depression. SAMe increases the synthesis of neurotransmitters, and those are the ones that are commonly associated with the treatment of depression. This includes dopamine, norepinephrine, and serotonin. SAMe acts like the so-called fabled triple reuptake inhibitor that pharmaceutical companies have been trying to find for years. It will increase the synthesis of these three major neurotransmitters involved in the pathophysiology of depression. There are additional benefits to using SAMe, including enhanced neuronal cell membrane fluidity. It also has antioxidant effects as well as anti-inflammatory effects, and there's a neuroprotective property which may contribute to the antidepressant effects of SAMe.  

Let's go into a little more detail about SAMe MOA. It was discovered in 1952 by an Italian biochemist. It's considered an endogenous intracellular, amino acid, metabolite, and enzyme cosubstrate. It's involved in multiple biochemical pathways. The most important is the synthesis of the monoamine neurotransmitters, but it's also involved in the biosynthesis of hormones. SAMe is what we call a universal methyl donor. It's involved in more than 100 methyltransferase reactions. It has the added benefit of increasing the uptake of phospholipids into the nerve cell membranes which is responsible for the increased fluidity and enhanced neurotransmission.

Let's talk a little bit about deficiencies associated with reduced SAMe levels. This is important to note because as you can see here in this diagram, what we're looking at is the methylation cycle. SAMe is acting in this process. I want to turn your attention to important cofactors for the synthesis of SAMe. In order to synthesize SAMe, you need vitamin B12 as a cofactor. If a person or a patient is deficient in B12. they're not going to be synthesizing SAMe appropriately. This also is another place where you may intervene because you may not only recommend the person take SAMe, but you may add B12 as well. Deficiencies of SAMe of B12 in depression and neurocognitive disorders may explain the benefit of supplementing with these products. 

SAMe has the most evidence to support its use in depressive disorders, either as a monotherapy or adjunctive therapy for depression. SAMe has been studied in animal models for depression, and when we administer SAMe to the rodents, it results in increased concentrations of central nervous system monoamine neurotransmitters. One trial looked at SAMe and found that it has a dose-dependent decrease in immobility time on the forced swimming test in rodents, a measure of depression in this animal model. 

The use in the treatment of depression is supported by over two dozen-controlled trials and systematic reviews. The weakness in this evidence base is a lack of large randomized controlled trials. The sample sizes tend to be small with the number of participants being less than 100. When SAMe is compared head-to-head with other antidepressants, it performs as well as medication. A meta-analysis found that its overall effect size is 0.65 in the moderate range. This is significantly higher than what we see in most antidepressant trials where the effect size is roughly 0.3 for these medications.

SAMe in general performs as well as medication for the treatment of depression. Several randomized controlled trials compared SAMe to other antidepressants, including the TCAs and escitalopram. Overall, we have 18 randomized controlled trials of SAMe versus TCAs. What we find is SAMe is as effective as the TCAs for the treatment of depression. There was a meta-analysis of these 18 randomized controlled trials of SAMe versus TCAs which confirmed the equivalency of SAMe to TCAs for depression treatment. One large multicenter study compared SAMe to escitalopram over 12 weeks. In this trial they compared SAMe to both placebo and escitalopram and what the researchers found was the overall effect size was quite high. This study found an overall effect size of 0.74, and they found that SAMe outperformed placebo as early as week one. 

Another topic that we want to talk about is how SAMe works as an augmentation strategy in depression. Several studies support the use of SAMe as adjunctive treatment for major depression. There's one open-label trial, where they took participants with major depressive disorder who did not fully respond to serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors and added SAMe 800 mg per day for the first two weeks then they followed that up by 1600 mg per day for the remaining four weeks. At the end of the six weeks there was a 50% response rate and 43% remission rate among the participants. In another randomized controlled trial of non-responders or partial responders to antidepressants participants were randomized to receive either 1600 mg per day of SAMe or placebo for six weeks. Both response and remission rates were higher for those receiving SAMe. The response for SAMe was 36.1% versus placebo at 17.6% and remission for SAMe was 25.8% versus placebo at 11.7%. The research indicates that SAMe can be safely combined with most classes of antidepressants including MAOIs but there is a theoretical risk of serotonin syndrome. Careful monitoring is required. 

When would you want to avoid using SAMe? The one place to avoid SAMe is in bipolar depression, there have been some case reports of SAMe causing mania. There's also little evidence to support the use of SAMe and treatment resistant depression. 

Let's look at SAMe for depression associated with medical illness. The anti-inflammatory, the antioxidant, and neuroprotective properties may all play a role in these situations. If you've followed The Carlat Psychiatry Report, there's a lot of recent data published on depression and inflammation. It would not be a far stretch for us to imply that those with elevated inflammatory markers such as C-reactive protein would benefit more from SAMe treatment than those who do not have elevated inflammatory markers. Depression associated with any disease process that causes inflammation may benefit more because of the anti-inflammatory effects of SAMe.

SAMe is particularly effective in the treatments of depression associated with medical illness. It's been looked at in several diseases. We can look at depression associated with Parkinson's disease, depression associated with neurocognitive disorders, and depression associated with HIV. What's interesting about all three of these examples is that each of these disorders has been associated with low SAMe levels in the cerebral spinal fluid.

There is an eight-week open-label study of 20 HIV positive individuals with major depressive disorder who are all treated with 800 to 1600 mg/day of SAMe. There was a significant reduction in baseline depression scores. The mean Hamilton Depression Inventory (HAM-D) score at baseline was 33.5 and the mean HAM-D score at the end of the study was 26.5. At eight weeks, the remission rates were 93% for the 15 participants who completed the study. 

What about using SAMe for depression associated with Parkinson's disease? As many as 30% to 50% of those diagnosed with Parkinson's disease experience depression, we also know that treatment of that depression can be quite complex given the fact that there are many drug interactions that can greatly limit the use of antidepressant medications in this population. Patients with Parkinson’s disease have low SAMe levels in their CSF. There are a total of three trials which used higher doses of SAMe. In these trials there was a significant reduction in HAM-D scores. Another 10-week open-label study produced similar results with significant reductions in HAM-D scores. Administration of 800 to 3600 mg/day of SAMe also proved to be as effective as escitalopram in a 12-week randomized controlled trial of depression associated with Parkinson's disease.

Major depression is commonly associated with neurocognitive disorders. A one-year open label study of early-stage Alzheimer's disease looked at SAMe combined with other nutraceutical products. Specifically, they combined SAMe with folic acid and B12. The study demonstrated an improvement in cognitive symptoms that were assessed by the dementia rating scale and by the clock drawing test. The interpretation of these results is somewhat limited because the researchers combined SAMe with other supplements. 

The final one to talk about here is SAMe for depression and chronic pain. Chronic pain is associated with depression, and it's often difficult to treat clinically. Disorders like osteoarthritis and fibromyalgia are associated with depression and SAMe's mechanism of action includes both anti-inflammatory and analgesic benefits. In osteoarthritis, SAMe provided pain relief comparable to nonsteroidal anti-inflammatory (NSAIDS) in one large, randomized head to head trial. In three out of the four placebo-controlled trials for fibromyalgia, significant pain relief occurred with SAMe treatment. 

We need to know how to prescribe SAMe and how to dose it effectively to achieve the desired result. The typical starting dose is 400 mg/day, and it can be raised by 200 to 400 mg every three to seven days. We're going for a target dose of 800 mg to 1600 mg/day. 

What about the side effects? Side effects from SAMe are generally mild, but patients should be aware of them. The most common side effects are things like nausea, vomiting, abdominal discomfort, and diarrhea. SAMe can induce anxiety, insomnia, and potentially induce mania in patients with bipolar depression. It is recommended to start low and go slow with the dose titration. Patients with a history of cardiac arrhythmia or those who are pregnant should use caution when adding SAMe to their treatment. 

ConsumerLab.com has tested several brands for purity and potency and the ones that we can most reliably recommend are Doctors Best, Nature's Trove, NOW, Swanson's, Vitacost and Vitamin Depot. All of these are reasonable options. And they all come at a cost of $27 to $40 per month for an 800-mg dose.

I'm going to go ahead and conclude this webinar here. I'm happy that I had the opportunity to present this data to you.

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The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one-half (.5) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.