TOP DEPRESSION EXPERT, RESEARCHER, AND AUTHOR SHARES FINE SAM-E AND ESCITALOPRAM [LEXAPRO] RESULTS

To our knowledge, this is the first study to examine the effectiveness of a dose increase of SAMe for patients with MDD who failed to respond to an initial dose. While there were no significant differences in effectiveness among SAMe 3,200 mg/day, escitalopram 20 mg/day, and placebo, increased doses of SAMe and of escitalopram provided improvement for nonresponders in various rating scales, which might be a time-related rather than dose-related improvement. Effect sizes recorded for changes in the HDRS-17 scale in the dose increase period were in the medium range at 0.51 for SAMe and 0.65 for escitalopram. Notably, placebo also produced a continued improvement in the dose increase phase, with significant outcomes in all four outcome measures, and an effect size of 0.69 per the HDRS-17 scale. This robust placebo effect may have been due to a relative enrichment in factors that have been shown to be associated with an increased response to placebo (Trivedi et al., 2018). Likewise, there were no significant differences in subsequent effective outcome among responders to SAMe 1,600 mg/day, escitalopram 10 mg/day, and placebo. Maintaining initial dose would therefore be reasonable choice for responders to SAMe and escitalopram in clinical settings, particularly with a view toward minimizing risk of new or worseningside effects.

The findings are complicated by the fact that there was a trend-level improvement in the SAMe group by week 10 in the mixed-effects model for repeated measures, and this was apparently lost by week 12. This was similar to the pattern seen in the parent study, where SAMe significantly separated from placebo at weeks 8 and 10, followed by the loss of significance by week 12. This effect may have to do with psychological worsening on the part of the patients as they face termination in the study and uncertainty about what may await them regarding their condition and clinical care (Mischoulon et al., 2014).

Furthermore, it should be noted that participants in this study may have been more depressed than what is considered optimal severity for SAMe treatment. According to reviews of published articles so far, general clinical recommendations for SAMe monotherapy suggest targeting patients with mildly symptomatic depression who do not necessarily require a prompt effective antidepressant treatment (De Berardis et al., 2016). Non-response to previous treatment or moderate severity of illness (which is reflective of our study sample, with each arm having mean baseline HDRS-17 scores in the range of 18–19, indicating moderate depression) may not represent a good indication for SAMe treatment, though in previous studies, subjects improved with addition of SAMe despite moderate severity of illness and earlier non or partial response to SSRIs and SNRIs (Alpert et al., 2004; Papakostas et al., 2010).

The effectiveness of SAMe may vary according to subjects’ pharmacokinetic variations. Cerebrospinal fluid (CSF) SAMe levels, which are low in patients with severe depression, have been reported to rise to normal level by intravenous SAMe 200 mg daily for 14 days (Bottiglieri et al., 1990). However, there are no data assessing the relationship between oral SAMe administration and CSF SAMe levels. SAMe may show efficacy only in cases of low baseline CSF levels, which were not assessed in this study. Additionally, while different nutraceuticals used for treating depression have a range of frequently used doses in clinical trials, these may not necessarily indicate the most effective doses (Mischoulon and Rapaport, 2018). In fact, dose-response relationships for depression remain unclear for many nutraceuticals. Only in the meta-analysis of omega-3 polyunsaturated fatty acid, the effective dose and combination of eicosapentaenoic acid and docosahexaenoic acid have been examined (Iovieno et al., 2011). More drug monitoring and dose-response research are necessary to investigate the contribution of a specific doses of nutraceuticals for depression.

In the present study, stomach or abdominal discomfort was reported most frequently with higher dose SAMe compared to the other higher dose treatments, which is consistent with our observations in the parent study (Mischoulon et al., 2014). While gastrointestinal symptoms as well as sweating, vertigo dizziness, irritability, insomnia, tachycardia, restlessness, and anxiety have been often reported in past studies, SAMe treatment has generally been considered safe and well tolerated (De Berardis et al., 2016). This discrepancy probably occurs because previous studies are limited to doses of 1,600 mg/day or less of SAMe, and this study represents the first trial testing 3,200 mg/day of SAMe. While this preliminary finding must be reproduced in larger studies, caution should likely be undertaken by clinicians who are considering increasing the dose of SAMe in partial and non-responders to lower doses. On the other hand, it bears mention that no patient dropped out due to adverse events during the higher dose treatment, suggesting that tolerability was good overall.

This study has several limitations. First, the sample in the higher dose period in the present analysis was one-third as large of that from the parent study, which limits power to detect differences between treatments. Second, the duration of six weeks is relatively short to optimally compare the effectiveness and tolerance of the three higher dosing strategies, since antidepressants may require up to 8–12 weeks to produce a full effect. The treatment duration was selected based on what is known about response to antidepressants, usually occurring within 4–6 weeks (Nierenberg et al., 1995; Posternak et al., 2011), and also taking into account the burden on patients that a very long double blind trial of > 3 months represents, which can reduce adherence and completion rates. This may explain in part why response and remission rates during the higher dose SAMe and escitalopram treatments were only about half the level of those obtained with the step 2 treatments in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial (Rush et al., 2006). Third, since only patients who failed to respond to a certain starting dose of the allocated treatments were included, any extrapolation of these findings to other depressed populations or other doses must be made with caution. For example, these findings may not be extended to more severely depressed or treatment resistant populations than the one we studied, or to patients who start treatment on higher doses than ours.

In conclusion, we found that increasing the dose of SAMe to 3,200 mg/day and escitalopram to 20 mg/day produced additional but modest improvement over a 6-week treatment period in patients with MDD who did not respond to SAMe 1,600 mg/day or escitalopram 10 mg/day. Unfortunately, the high placebo effects prevent us from determining whether changes associated with doubling SAMe and escitalopram are purely time effects rather than dose effects. Of some concern, SAMe 3,200 mg/day resulted in the most frequently reported abdominal discomfort among the investigated higher dose treatments, but this did not appear to result in any early terminations from the study, suggesting that the benefit may outweigh the discomfort. We still need to better characterize the overall efficacy of SAMe compared to standard antidepressants. Clinicians whose patients are using SAMe for depression should carefully consider the pros and cons of dose increases beyond 1,600 mg/day in cases of non-response at this dose or when deciding whether to pursue further optimization in patients who respond well to 1,600 mg/day. Further research is needed in larger samples and for longer study periods to develop more effective dosing strategies.

Highlights.

• A dose increase of S-adenosyl methionine (SAMe) in depression was examined.

• Symptoms in non-responders improved after a dose increase from 1,600 to 3,200 mg/d.

• No significant difference in efficacy was found between each SAMe dose.

• No superiority was found among SAMe 3,200 mg/d, escitalopram 20 mg/d, and placebo.

• Abdominal discomfort was reported most frequently with SAMe 3,200 mg/d treatment.