CanJPsychiatry 2012;57(7):406413

In Review

Folates and S-Adenosylmethionine for Major Depressive Disorder

George I Papakostas, MD1; Clair F Cassiello, BA2; Nadia Iovieno, MD, PhD3
1

Associate Professor of Psychiatry, Harvard Medical School and Director of Center for Treatment-Resistant Depression, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Correspondence: Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, One Bowdoin Square, Boston, MA 02114; gpapakostas@partners.org. Research Assistant, Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Research Fellow, Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Key Words: major depressive disorder, S-adenosylmethionine, folate, L-methylfolate, antidepressant therapy, augmentation therapy Received November 2011 and accepted December 2011.

Interest in nonpharmaceutical supplements for treating major depressive disorder (MDD) has increased signicantly, both among patients and among clinicians during the past decades. Despite the large array of antidepressants (ADs) available, many patients continue to experience relatively modest response and remission rates, in addition to a burden of side effects that can hinder treatment compliance and acceptability. In this article, we review the literature on folates and S-adenosylmethionine (SAMe), 2 natural compounds linked in the 1-carbon cycle metabolic pathway, for which substantial evidence supports their involvement in mood disorders. Background information, efcacy data, proposed mechanisms of action, and side effects are reviewed. Based on existing data, supplementation with SAMe, as well as with various formulations of folates, appears to be efficacious and well tolerated in reducing depressive symptoms. Compared with other forms of folates, 5-methyltetrahydrofolate (L-methylfolate or 5-MTHF) may represent a preferable treatment option for MDD given its greater bioavailability in patients with a genetic polymorphism, and the lower risk of specific side effects associated with folic acid. Although further randomized controlled trials in this area appear warranted, SAMe and L-methylfolate may represent a useful addition to the AD armamentarium. WWW Lintrt port aux supplments non pharmaceutiques pour traiter le trouble dpressif majeur (TDM) sest accru significativement, tant chez les patients que chez les cliniciens au cours des dernires dcennies. Malgr la vaste gamme dantidpresseurs (AD) offerte, nombre de patients nont toujours quune rponse et des taux de rmission relativement modestes, en plus dun fardeau deffets secondaires qui peuvent nuire lobservance et lacceptabilit du traitement. Dans cet article, nous examinons la littrature sur les folates et la S-adnosylmthionine (SAMe), 2 composs naturels lis dans la voie du mtabolisme monocarbon, dont la participation aux troubles de lhumeur est appuye par des donnes probantes substantielles. Les renseignements gnraux, les donnes sur lefficacit, les mcanismes daction proposs, et les effets secondaires sont examins. Selon les donnes existantes, la supplmentation avec la SAMe, ainsi quavec diverses formules de folates, semble tre efficace et bien tolre pour rduire les symptmes dpressifs. Compar dautres formes de folates, le 5-mthylttrahydrofolate (L-methylfolate ou 5-MTHF) peut reprsenter une option de traitement prfrable du TDM, tant donn sa biodisponibilit chez les patients ayant un polymorphisme gntique, et le faible risque deffets secondaires spcifiques associs lacide folique. Bien que dautres essais randomiss contrls dans ce domaine semblent tre ncessaires, la SAMe et le L-mthylfolate peuvent reprsenter un ajout utile larsenal thrapeutique des AD.

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Folates and S-Adenosylmethionine for Major Depressive Disorder

espite the large array of AD agents available, many patients treated for MDD continue to experience relatively modest rates of response and remission, in addition to a side effect burden that can hinder treatment compliance and, in some patients, may also contribute to increased functional impairment (for example, sedation and cognitive side effects), increased sense of subjective suffering, increased morbidity (for example, obesity), and mortality. To enhance treatment efficacy and tolerability, patients and clinicians have become increasingly interested in nonpharmaceutical supplements for treating MDD. Among the most studied of these supplements are folate, L-methylfolate, and SAMe, which are linked in the common metabolic pathway of the one-carbon cycle.

Clinical Implications
Nonpharmaceutical supplements may be a treatment option for patients with MDD who cannot tolerate or do not accept standard AD therapy. Ample evidence supports the involvement of onecarbon cycle dysregulation in MDD. L-methylfolate and SAMe appear efficacious and well tolerated in treating MDD, especially as augmenting agents to a first-line AD therapy. Depressed patients with both low and normal folate levels may benefit from L-methylfolate augmentation. Most studies on SAMe involved parenteral administration and comparison with TCAs. There is limited information about optimal dosing regimens for SAMe as well as drugdrug interactions. More large, well-conducted RCTs on SAMe and L-methylfolate for the treatment of MDD are warranted.

Limitations

The Role of Folate, L-Methylfolate, SAMe, and the One-Carbon Cycle in MDD

The one-carbon cycle is the metabolic pathway that involves the conversion of dietary folate or folic acid into SAMe via several intermediary molecules, including L-methylfolate (also known as 5-methyltetrahydrofolate or 5-MTHF). SAMe is found throughout the human body, with particularly high concentrations in the liver, adrenal glands, and the pineal gland1,2 where it serves as the major donor of methyl groups required in the methylation of a diverse number of targets, including phospholipids, DNA, ribonucleic acid, neurotransmitters, and proteins.3 Abbreviations
5-HT AD BDI bid C677T CNS CSF DA DNA HDRS ITT MAT MDD MTHFR NE NNT RCT SAMe SD4 SNRI SSRI TCA www.TheCJP.ca serotonin antidepressant Beck Depression Inventory bis in die (twice daily) C-to-T substitution at nucleotide 677 of the MTHFR gene central nervous system cerebrospinal fluid dopamine deoxyribonucleic acid Hamilton Depression Rating Scale intention-to-treat methionine adenosyltransferase major depressive disorder methyltetrahydrofolate reductase norepinephrine number needed to treat randomized controlled trial S-adenosylmethionine 1,4 butanedisulfonate serotonin norepinephrine reuptake inhibitor selective serotonin reuptake inhibitor tricyclic AD

Folate is a water-soluble B vitamin, considered 1 of the 13 essential vitamins. The primary function of folate is the transfer of methyl and formyl groups, which is essential for cell growth and reproduction, the breakdown and use of proteins, the formation of nucleic acids, red blood cell maturation, and various CNS reactions. Dihydrofolate is the dietary form found in many foods, including leafy vegetables, legumes, fruit, yeast, and eggs. Folic acid is the synthetic form of folate in over-the-counter vitamins and used to fortify the food supply. Both folic acid and dihydrofolate are not biologically active forms of folate, and must undergo enzymatic transformation to L-methylfolate to be used by cells, as L-methylfolate readily crosses the bloodbrain barrier for use in the CNS. L-methylfolate then joins with homocysteine to form methionine, which is then metabolized by MAT, along with vitamin B12, to form SAMe. Homocysteine is a byproduct of the one-carbon cycle; when homocysteine levels build up in human cells, it serves to inhibit one-carbon cycle metabolism. Several hypotheses have been proposed for the AD mechanisms of folate and SAMe in the human body. One hypothesis is that, by methylating plasma phopholipids, SAMe may alter the fluidity of the neuronal membrane, thereby affecting the function of proteins that transverse the membrane, including various monoamine receptors, monoamine transporters, and other elements of the second messenger system.4 Alternatively, several studies suggest a link between one-carbon cycle metabolism and monoamine neurotransmitter synthesis.1,5 In fact, previous studies reveal a correlation between low red cell folate levels and low CSF metabolites of DA, NE, and 5-HT in MDD.6 Thus it is also possible that low SAMe levels may result in decreased monoamine synthesis, which may contribute to an increased risk of depression or treatment-resistance in hypofolatemic patients.
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L-methylfolate 5-methyltetrahydrofolate or 5-MTHF

In Review

There is ample evidence to suggest a link between MDD and changes in enzymes, catalysts, or co-factors involved in the one-carbon cycle. Many studies have linked MDD with low folate levels713 and lower L-methylfolate concentrations.14 Depressed subjects with low folate appeared to have diminished CSF levels of SAMe,5 whereas the folate concentration of erythrocytes was found to directly correlate with CSF 5-hydroxyindoleacetic acid and homovanillic acid levels.6 Depressed subjects with low folate also appeared to have greater severity of depression9,14 and poorer response to various ADs and augmentation strategies.9,1520 In fact, a greater degree of change of erythrocyte folate concentrations during treatment was found to correlate with a greater decrease in HDRS scores, and greater erythrocyte folate concentrations after treatment were observed in responders than in nonresponders.9,20 Further, depressed adults treated with electroconvulsive therapy, ADs, or tryptophan, with lower pretreatment serum folate levels, were found to have higher depression ratings after treatment than patients with normal folate levels.21 Additionally, vitamin B12 deficiency is commonly linked to many neuropsychiatric disorders, including MDD.12,22,23 Alarcon et al24 reported that the erythrocytes of patients with MDD had lower levels of activity of the MAT enzyme, compared with control subjects, while, in another study,25 treatment with ADs resulted in an increase in MAT activity. Studies also report a relation between elevated homocysteine levels and depressive disorders.12,26 Further, elevated homocysteine levels in MDD have been associated with low folate levels, low SAMe levels, and low CSF levels of the 5-HT, DA, and NE metabolites.5 There are several genetic studies linking enzymes involved in the one-carbon cycle and depression. A certain mutation (C677T) of the MTHFR gene, for instance, which is responsible for an enzyme with less that 50% specific MTHFR activity, has been identified.27 This polymorphism is quite prevalent in MDD, and is more commonly found in patients with MDD than in control subjects.2632 Although not all studies have been positive, a statistically significant association between MDD and the C677T polymorphism has been confirmed by several meta-analyses.31,3335 There is also a report of the presence of this polymorphism and poor treatment response to the SSRI citalopram in patients with depression secondary to traumatic brain injury,36 as well as a report linking the polymorphism with psychomotor speed in elderly depressed patients.37 Therefore, as L-methylfolate enters the one-carbon cycle downstream from MTHFR (meaning that MTHFR is not required for the ultimate conversion of L-methylfolate into SAMe, while dietary folates are), and in light of the prevalence of MTHFR mutations in MDD, the use of L-methylfolate may represent a preferable treatment option, compared with other folate forms for MDD.
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Link Between Abnormalities in Elements of the One-Carbon Cycle and MDD

Clinical Evidence for a Potential Role for Folate, L-Methylfolate, and SAMe in the Treatment of MDD
Clinical Trials of Folate and L-Methylfolate in MDD

Studies of Folate and L-Methylfolate as Monotherapy for MDD. Four studies have examined folate monotherapy in MDD. A double-blind study38 compared 50 mg/day of L-methylfolate with 150 mg/day of amitriptyline in 31 outpatients with moderate MDD and mostly normal folate levels during 6 weeks, after a 2-week placebo run-in phase to eliminate placebo responders. Similar response rates were found between the groups, but, among those who took L-methylfolate, the responders showed increased folate levels, compared with nonresponders. In another double-blind study,39 L-methylfolate was compared with trazodone in elderly depressed patients with mild-to-moderate dementia and normal folate levels. After a 2-week placebo run-in, nonresponders (n = 96) were randomly assigned to 50 mg/day of L-methylfolate or 100 mg/day of trazodone for 8 weeks. Partial to complete response to AD treatment was seen in a greater percentage of patients who received L-methylfolate than in those who received trazodone. In one open study40 patients aged 60 years and older with MDD (n = 20) received 50 mg/day of L-methylfolate for 6 weeks. Only 2 patients had low folate levels at baseline. A statistically significant improvement was seen in HDRS from baseline at week 1 (P < 0.01), and became more robust during the 6 weeks (P < 0.001), with mean HDRS-21 scores decreasing from 34.8 at baseline to 9.9 at end point. Overall, the response rate for L-methylfolate was 81%. In another open study,41 inpatients with MDD and chronic alcoholism (n = 36) were treated for 4 weeks with 30 mg/3 times daily L-methylfolate. No adverse events were reported. Mean HDRS-21 scores fell from 35.3 at baseline to 18.8 at end point (P < 0.01) and were statistically significant, compared with baseline, by week 2. Significant improvement in well-being and reduction in fatigue and pain from baseline to week 4 were also reported. Studies of Folate and L-Methylfolate as Adjunctive Therapy for MDD. Several RCT studies explored whether the addition of folate to the psychopharmacologic regimen of patients with MDD can improve outcome. Godfrey et al42 randomized 24 hypofolatemic patients with MDD to receive cotherapy with ADs and L-methylfolate (15 mg), compared with AD monotherapy. In this 6-month, double-blind RCT, the 13 depressed patients who received L-methylfolate were rated globally as having superior symptom improvement and social adjustment after 3 and 6 months, compared with the 11 patients assigned to placebo. In a subsequent double-blind study, Coppen and Bailey43 reported higher response rates among 127 patients with first-episode MDD treated for 10 weeks with fluoxetine
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Folates and S-Adenosylmethionine for Major Depressive Disorder

plus folic acid (500 g) cotherapy, compared with patients who received fluoxetine monotherapy (plus placebo). Interestingly, while a significantly greater percentage of women who received folic acid responded, compared with those who received placebo (P < 0.005), folic acid in men did not separate from placebo as an augmenting agent. More recently, a third, smaller (n = 27) double-blind RCT study44 also demonstrated a greater resolution of depressive symptoms among patients with MDD treated with the combination of fluoxetine (20 mg) plus folic acid (10 mg) than those treated with fluoxetine alone. In a study of lithium and folate,45 patients (n = 75; 53 with unipolar depression, 17 with bipolar depression, and 4 with schizoaffective disorder) who were being treated with lithium received 200 g/day of folate or placebo for 1 year. Patients whose plasma folate was 13 ng/mL or more at end point had a 40% or more reduction in Affective Morbidity Index scores during the 1-year trial period. Among patients with unipolar depression who received folate, a small but significant reduction in scores on the BDI occurred during the trial (P < 0.02), whereas those receiving placebo experienced a small increase in BDI scores. To date, 3 clinical trials explored the use of folate augmentation in patients with treatment-resistant depression. In an open-label study,46 adults with SSRI-resistant MDD (n = 22) were enrolled in an 8-week prospective trial with folinic acid (1530 mg/day). Among the completers and the ITT groups, mean HDRS-17 scores decreased significantly from baseline to end point. Among the completers and the ITT samples, 31% and 27%, respectively, achieved response, and 19% and 18%, respectively, achieved remission. Papakostas et al47 conducted 2 separate trials, identical in design except for differences in L-methylfolate dosing, focusing on adjunctive L-methylfolate for AD-resistant patients with MDD. In these 60-day, double-blind, multicentre trials, outpatients with SSRI-resistant MDD were randomized to receive adjunctive L-methylfolate, dosed either at 7.5 mg/day or placebo (n = 148) or at 15 mg/day or placebo (n = 75). While no difference in the degree of depressive symptom resolution or in the response rates between the 2 treatment groups was found in the lowerdose trial (7.5 mg daily), results of the second trial showed a significant greater efficacy for adjunctive 15 mg/day L-methylfolate, compared with continued SSRI therapy plus placebo, with response rates of 32.3% and 14.6% for L-methylfolate and placebo, respectively (P = 0.04). The NNT for response in the study was between 5 and 6 in favour of adjunct L-methylfolate, compared with placebo, which is comparable to NNTs reported for other augmentation strategies in MDD, such as the atypical antipsychotic agents and lithium.48,49
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Safety and Tolerability of Folate and L-Methylfolate

Folate is generally safe and well tolerated, with all reported adverse events occurring at placebo rates or lower. However, the development of manic symptoms in 1 patient receiving 15 mg adjunctive L-methylfolate has been reported.47 Historically, the greatest concern with folate supplementation has been its ability to mask vitamin B12 deficiency. In fact, folic acid supplementation corrects the anemia of B12 deficiency and may conceal the continuing lack of B12, thus delaying the diagnosis and leaving the patient vulnerable to permanent nervous system damage. However, L-methylfolate is unable to synthesize DNA and, therefore, is not expected to mask B12 deficiency.50 Another concern is the increase risk of cancer. In fact, high amounts of unmetabolized folic acid can contribute to carcinogenesis51 because it bypasses the demethylation reaction required for natural folates and can contribute directly to the synthesis of nucleotides, which are used for DNA synthesis by proliferating cells. Studies conducted both in animals and in humans have found an association between high folate intake and colorectal cancer risk,52,53 although more recent studies50,54,55 do not support such an association, and the benefits of folate supplementation probably outweigh the risks of cancer.56 Another concern is that folate doses in excess of 800 g/day can result in high levels of unmetabolized serum folic acid, reducing the amount of brain L-methylfolate and leading to decreased monoamines, an outcome that potentially increases the risk of, or exacerbates, depression. Again, the findings are mixed, but, in people for whom this is a concern, L-methylfolate may be less likely to incur these risks.50,56,57

Clinical Trials of SAMe in MDD

Although SAMe has been marketed for more than 25 years in Europe as an AD, it was released in the United States as an over-the-counter dietary supplement under the Dietary Health and Supplement Act only in 1999. The AD effects of SAMe were first noted serendipitously in the early 1970s,58 an observation that was soon followed by several openlabel studies of parenteral SAMe for patients with MDD that showed promising results.5965 To date, SAMe has been studied in more than 45 RCTs involving depressed adults in Europe and the United States.66 These studies have used parenteral and oral preparations of SAMe toluenesulfonate (SAMe tosylate) and, to a lesser extent, SAMe SD4. Studies of SAMe as Monotherapy for MDD. Several double-blind RCT studies showed that parenteral SAMe, administered at doses ranging from 150 mg/day to 400 mg/day, was generally equally or more effective than standard TCAs, such as clomipramine, amitriptyline, and imipramine, and tended to produce an earlier response (often within 3 to 7 days) and fewer side effects.6771 More recently, 2 large studies of depressed outpatients72,73 found
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In Review

that 400 mg/day of intramuscular SAMe for 4 weeks was as efficacious as 150 mg/day of oral imipramine for 6 weeks. Several studies have compared the use of parenteral SAMe with placebo in MDD. Five small studies (n 40),62,71,7476 conducted between 1976 and 1988, reported that intravenous (200400 mg/day) or intramuscular (45 50 mg/day) SAMe was more effective than placebo in the treatment of depression. Another study77 failed to demonstrate a superiority of 200 mg/day of intravenous SAMe, compared with placebo, in MDD overall, although a significant treatment effect in favour of SAMe was reported among the subset of patients with endogenous depression (n = 32). Finally, in the largest study published to date (n = 60) comparing parenteral SAMe with placebo, Caruso and Pietrogrande78 demonstrated that 200 mg/day of intravenous SAMe was superior to placebo in the treatment of outpatients with MDD and comorbid rheumatoid arthritis. Although these studies indicate that parenteral SAMe is more effective than placebo, and equivalent in efficacy to the TCAs, in the treatment of MDD, the route of administration (that is, intravenous or intramuscular) considerably limits the clinical usefulness of these findings. However, the administration of SAMe orally is associated with a significant rise of CSF SAMe, suggesting that it crosses the bloodbrain barrier.79,80 Overall, in controlled clinical trials of oral SAMe, doses have generally been between 800 and 1600 mg/day in divided doses, although there has been no systematic exploration of dose response. Three double-blind RCTs have examined the use of oral SAMe, compared with a TCA, for MDD. Two small studies (n 26)81,82 and a large study (n = 281)72 all demonstrated that 1600 mg/day of oral SAMe was equivalent to a TCA in treating MDD. Three placebo-controlled studies have examined the use of oral SAMe as monotherapy for MDD. Two of these studies83,84 demonstrated that the AD effects of 1600 mg/day of oral SAMe were superior to those of placebo among patients with MDD, respectively, in a population of depressed, postmenopausal women and inpatients with MDD. However, the third study85 showed the same dosage of SAMe to be no more effective than placebo. This study noted that the particular oral preparation of SAMe (SD4) used was a relatively unstable formulation for clinical use, and may have been responsible for the absence of a significant treatment effect in that study. In fact, shortly after the completion of that trial, the US Food and Drug Administration stopped clinical trials of SD4 at US sites because of issues regarding the poor dissolution of the tablets. A 2002 meta-analysis66 commissioned by the Agency for Healthcare Research and Quality, showed that when data from 28 evaluable RCTs of intramuscular, intravenous, and oral SAMe as monotherapy treatment for MDD were pooled, SAMe was associated with an overall effect size of 0.65 (95% CI 1.05 to 0.25), compared with placebo, which translated to an improvement in the HDRS scores of
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almost 6 points. In comparing SAMe to TCAs, the metaanalysis found an effect size of 0.08 (95% CI 0.17 to 0.32), indicating that treatment with SAMe for MDD is about equivalent to treatment with TCAs. Sudies of SAMe as Adjunctive Therapy for MDD. Alpert et al86 conducted an open-label trial to examine the efficacy of oral SAMe as an adjunctive treatment for 30 outpatients with MDD who had not experienced significant symptom improvement following open-label treatment with either an SSRI or venlafaxine. Patients received 400 mg/bid of SAMe for the first 2 weeks of the trial, followed by 800 mg/bid for an additional 4 weeks. In the ITT analysis, 50% of the patients responded during the course of therapy, and 43% remitted. The decrease from baseline in depressive symptom severity reached significance by week 1 and remained significant through week 6 (P < 0.001). Of note, patients experienced a significant decrease in homocysteine levels during the course of treatment, from 8.2 to 7.8 mol/L (P = 0.003). A double-blind, placebo-controlled RCT evaluated the use of parenteral SAMe as an adjunctive therapy in MDD. In this 2-week study,87 AD-naive patients (n = 40) were assigned to receive either 200 mg/day of intramuscular SAMe or a placebo injection in adjunction to imipramine, which was titrated to 150 mg/day by the end of the first week. By day 4, patients receiving both SAMe and imipramine had experienced a significant advantage in AD effect, compared with the monotherapy group (P < 0.05); the advantage continued to be significant through day 12 of treatment, although not at day 14. These preliminary results suggest that the use of SAMe, when combined with ADs from the onset of therapy, may accelerate symptom improvement in MDD. In a recent, small pilot study, Papakostas et al88 randomized 73 patients with MDD, who were partial responders or nonresponders to SSRIs or SNRIs, to receive treatment with adjunctive SAMe (up to 800 mg/bid), compared with placebo, for a total of 6 weeks. Patients continued to receive their SSRI or SNRI treatment at a stable dose throughout the 6-week trial. Response and remission rates were higher for patients treated with adjunctive SAMe (36.1% and 25.8%, respectively) than with adjunctive placebo (17.6% and 11.7%, respectively) (P < 0.05), without statistically significant difference in the proportion of SAMe- and placebo-treated patients who discontinued the trial.

Studies published to date suggest that SAMe is generally well tolerated, with adverse effects such as mild insomnia, lack of appetite, constipation, nausea, dry mouth, sweating, dizziness, and restlessness.66 In the largest trials of SAMe monotherapy,72,73 considerably fewer patients receiving either oral or intramuscular SAMe reported side effects than patients receiving TCAs. However, psychiatric effects, such as increased anxiety, have been reported, as well as
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Safety and Tolerability of SAMe

Folates and S-Adenosylmethionine for Major Depressive Disorder

possible exacerbation or unmasking of manic or hypomanic symptoms in patients with bipolar depression.89 Although a report of putative 5-HT syndrome in an elderly patient treated with imipramine and SAMe suggests caution in coadministration of SAMe with SSRIs,90 the 2 recent trials of SAMe augmentation of SSRIs or venlafaxine86,88 reported that such combination was generally well tolerated, with no incidence of 5-HT-syndrome or unmasking of hypomanic or manic symptoms. The most common side effects reported in these augmentation trials were gastrointestinal symptoms and musculoskeletal side effects, such as headaches, anxiety, irritability, fatigue, and sedation. No significant changes in weight or increases in the severity of sexual dysfunction occurred during the course of the trials, although a slightly higher mean supine systolic blood pressure reading was observed in patients treated with adjunctive SAMe, relative to placebo.88

from Abbott Laboratories, Astra Zeneca PLC, BristolMyers Squibb Company, Brainsway Ltd, Cephalon Inc, Dey Pharma, LP, Eli Lilly Co, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Theracos, Inc, Titan Pharmaceuticals, and Wyeth Inc, and he has received research support from AstraZeneca PLC, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB LLC, Pfizer Inc, and Ridge Diagnostics (formerly known as Precision Human Biolaboratories). Finally, Dr Papakostas has served (in the past, but not currently) on the speakers bureau for BristolMyersSquibb Co and Pfizer, Inc. The Canadian Psychiatric Association proudly supports the In Review series by providing an honorarium to the authors.

Conclusions

Ample evidence supports the use of SAMe and several folate forms, in particular L-methylfolate, as efficacious and well-tolerated treatments for MDD. In particular, L-methylfolate appears to be an effective augmenting agent to first-line AD therapy, used either from the start of treatment or for AD partial responders and nonresponders. Depressed patients with both low and normal folate levels may benefit from L-methylfolate augmentation, especially as peripheral folate levels may not reflect CNS folate levels. As for SAMe, many studies have involved parenteral administration, and direct comparisons with the ADs currently used as first-line agents (that is, SSRIs) are lacking. The most widespread clinical use for SAMe may be as an oral augmenting agent for AD nonresponders, although, to date, only one double-blind, placebo-controlled RCT examining this usage has been published, and there is limited information about optimal dosing regimens as well as drugdrug interactions. Although further RCTs in this area appear warranted, SAMe and L-methylfolate may have several advantages as a treatment for MDD owing to their relative safety, tolerability, and novel mechanism of action, and may represent a useful addition to the AD armamentarium.

References

Acknowledgements

Dr Iovieno and Ms Cassiello report no relevant funding or support that may represent a conict of interest on this paper. Dr Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca PLC, Brainsway Ltd, Bristol-Myers Squibb Company, Cephalon Inc, Dey Pharma, LP, Eli Lilly Co, GlaxoSmithKline, Evotec AG, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Otsuka Pharmaceuticals, PAMLAB LLC, Pfizer Inc, Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Theracos, Inc, and Wyeth, Inc. He has received honoraria
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