Tips and pearls

SAMe has initial controlled data suggesting it can act as an augmentation in MDD

Another nutraceutical, L-methylfolate, also has controlled data suggesting effectiveness at 15 mg/d

St. John’s Wort might be an alternative

N-acetyl cysteine (NAC) 1000 mg twice daily is another alternative

Before advocating or utilizing a nutraceutical, review the apparent literature for its stringency

Two-minute tutorial

A primer on SAMe

SAMe is easier to say than its official chemical name, S-adenosyl methionine

SAMe, folate, vitamin B₁₂, and homocysteine are linked in the one-carbon cycle that is often memorized in the first year of medical school, usually after the Krebs cycle is learned

Many students who plan on going into psychiatry have worked out that memorizing these pathways is a way to graduate medical school and that knowledge of these metabolic pathways will never, ever be needed in psychiatry!

• – This would be an error in judgment now

SAMe is found throughout the human body, with particularly high concentrations in the liver, adrenal glands, and pineal gland

It is uniformly distributed in the brain, where it serves as the major donor of methyl groups required in the synthesis of neuronal messengers and membranes that have been implicated as being abnormal in mood disorders

The antidepressant efficacy of SAMe has been studied in randomized controlled trials involving depressed adults in Europe and the United States, utilizing both parenteral and oral formulations

Several potential mechanisms of antidepressant action have been theorized

• – It functions primarily as a methyl donor in a variety of biochemical reactions, including the methylation of catecholamines. Here, SAMe may promote greater synthesis and production of NE, DA, and 5-HT. This effect may be called trimonoamine modulation and provides a greater quantity of neurotransmitter for antidepressants to facilitate, possibly improving effectiveness

• – SAMe has been proposed to increase serotonin turnover, inhibit NE reuptake, and augment dopaminergic activity

• – Other investigations have suggested the presence of antidepressant mechanisms based on SAMe’s effects on brain neurotrophic activity, inflammatory cytokines, cell membrane fluidity, and bioenergetics, suggesting that SAMe may nurture neuronal plasticity and network formation

SAMe regulates and promotes methylation as discussed, and its formal pathway is depicted in Figure 24.1

The reactions that produce, utilize, and regenerate SAMe could be considered the “SAMe cycle”

• – First, SAMe-dependent methylase enzymes use SAMe as a substrate to produce S-adenosyl homocysteine

• – Next, this is hydrolyzed to homocysteine and adenosine by S-adenosyl homocysteine hydrolase and the homocysteine recycled back to methionine through transfer of a methyl group from 5-methyltetrahydrofolate methionine synthetase enzymes

• – This methionine can then be converted back to SAMe, completing the cycle

• – Regulation of this cycle can affect modulation of catabolic enzymes, monoamine transporters, and receptors, and thus is another means to regulate monoamine activity and theoretically improve MDD symptoms

Figure 24.1. Trimonoamine modulation (TMM) of L-5-methyl-tetrahydrofolate (MTHF) and S-adenosyl-methionine (SAMe): methylation and neurotransmitter synthesis.

Posttest self-assessment question and answer

Which of the following evidence-based antidepressant augmentations likely has the least side-effect burden?

A. SAMe

B. Lithium carbonate

C. Aripiprazole

D. Thyroid hormone

Answer: A

SAMe, as an over-the-counter CAM, likely has the least day-to-day side-effect burden and no known end organ damage risk compared to prescription medication augmentation strategies. Its evidence base, however, is less than that of the other agents. Lithium has end organ damage associated with renal dysfunction and hypothyroidism. The atypical antipsychotic, aripiprazole, is associated with TD and possible metabolic syndrome. Thyroid augmentations may be associated with inducing atrial arrhythmias such as flutter or fibrilliation that often require cardioversion.

References

1.Stahl SM. Stahl’s Essential Psychopharmacology, 4th edn. New York, NY: Cambridge University Press, 2013.

2.Stahl SM. Stahl’s Essential Psychopharmacology: The Prescriber’s Guide, 5th edn. New York, NY: Cambridge University Press, 2014.

3.Schwartz TL, Storman L, Thase M. Treatment outcomes with acute pharmacotherapy/psychotherapy Depression. In: Schwartz TL, Petersen T, eds. Treatment Strategies and Management, 1st edn. New York, NY: Informa, 2006.

4.Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M. S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. Am J Psychiatry 2010; 167:942–8.

5.Mischoulon D, Rosenbaum JF. Natural Medications for Psychiatric Disorders: Considering the Alternatives. Philadelphia, PA: Lippincott Williams & Wilkins, 2008.

6.Roje S. S-adenosyl-L-methionine: beyond the universal methyl group donor. Phytochemistry 2006; 67:1686–98.

7.Loenen WA. S-adenosylmethionine: jack of all trades and master of everything? Biochem Soc Trans 2006; 34:330–3.

8.Chiang PK, Gordon RK, Tal J, et al. S-adenosylmethionine and methylation. FASEB J 1996; 10:471–80.

9.Weissman MM, Markowitz JC, Klerman G. Comprehensive Guide To Interpersonal Psychotherapy. New York, NY: Basic Books, 2000.

10.Papakostas GI, Shelton RC, Zajecka JM, et al. L-methylfolate as adjunctive therapy for SSRI-resistant major depression: results of two randomized, double-blind, parallel-sequential trials. Am J Psychiatry 2012; 169:1267–74.

11.Müller WE. Current St. John’s wort research from mode of action to clinical efficacy. Pharmacol Res 2003; 47:101–9.

Patient file

The Case:

The combative business woman

The Question:

What to do when a patient becomes abruptly psychotic

The Dilemma:

The age-old functional versus organic differential diagnosis argument