Research reportS-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: Efficacy and effects of histamine and carnitine as moderators of response
Introduction
Major Depressive Disorder (MDD) is a common, typically recurrent and disabling disorder. Complementary and Alternative Medicine (CAM) use is prevalent by sufferers of mood disorders, with data from a nationally representative sample in the USA of 2055 people interviewed during 1997–1998 revealing that 54% of those with severe depression reported using CAM during the previous 12 months (Kessler et al., 2001).
S-adenosyl methionine (SAMe) is a naturally occurring substance synthesized from the amino acid l-methionine and adenosine triphosphate through the one-carbon cycle, a metabolic pathway that relies in part on adequate levels of folate and B12 (Spillmann and Fava, 1996, Papakostas, 2009). Routinely prescribed in Europe for nearly 30 years, SAMe has gained popularity in the U.S. following its release as an over-the-counter dietary supplement in 1998–1999 (Mischoulon and Fava, 2002). SAMe has been proposed as a potential treatment for a number of medical conditions, particularly MDD (Spillmann and Fava, 1996). Double-blind studies have demonstrated that parenteral or oral preparations of SAMe, compared with a number of standard tricyclic antidepressants (TCAs) such as clomipramine, amitriptyline, and imipramine, are generally equally effective, and tend to produce relatively fewer side effects (Bell et al., 1988, Della Chiaie and Boissard, 1997, Pancheri et al., 2002). Recent work from our group has supported efficacy of SAMe as an augmentation agent in partial and non-responders to SSRIs and SNRIs (Alpert et al., 2004, Papakostas et al., 2010).
One study thus far has compared the efficacy of SAMe versus both placebo and a standard selective serotonin reuptake inhibitor (SSRI) (Mischoulon et al., 2014). These types of studies are important because, while SAMe may demonstrate equivalency with a standard antidepressant, an inactive comparator is necessary to rule out placebo effects. Likewise, if the natural product outperformed placebo, we need to know how this would compare to an active comparator. Finally, given the widespread use of SSRIs as first line antidepressants, many efficacy studies of novel putative antidepressants will use SSRIs as the standard comparator.
One proposed explanation for a number of psychiatric disorders that may align with the neurobiological action of SAMe is the histadelic model (Pfeiffer et al., 1970, Edelman, 2001). This model suggests that mood and thought disorders may be caused, at least in some individuals, by elevated levels of histamine in the brain. Some studies have suggested that depression, bipolar disorder, schizophrenia, and drug abuse are associated with abnormal histamine levels, in some instances in as many as 20% of cases (Pfeiffer, 1988). Elevated levels of histamine have been associated with severe depression, easy crying, insomnia, obsessive-compulsive ruminations, and suicidality (Pfeiffer, 1988). Under-methylation and low serotonin have been implicated among the mechanisms involved in the presenting mood and thought abnormalities observed in histadelia (Pfeiffer, 1988, Edelman, 2001). Histadelic patients are not thought to respond well to conventional antidepressants or ECT. Investigation into the relationship between histadelia, depression, and response to treatment, could therefore prove valuable in the characterization and therapy of mood disorders.
Histamine is metabolized in part by SAMe, which methylates histamine׳s ring structure, thus forming N-methyl-histamine, a harmless metabolite (Pfeiffer, 1988, Edelman, 2001). Pfeiffer׳s model suggests that individuals with high levels of histamine would be especially likely to benefit from treatment with SAMe, and anecdotal data have supported this hypothesis. SAMe could potentially normalize histamine levels in the brain by methylating histamine. Conversely, depressed individuals with low or even normal histamine might not be expected to benefit as much from SAMe, assuming that histamine levels were playing a substantive role in their depression. Regardless, as SAMe modulates a range of neurochemical pathways, it still may be potentially effective in persons with low histamine.
Histadelia may also be relevant to mood disorder mechanisms because elevated histamine also results in low serotonin (Edelman, 2001). It is therefore possible that administration of SSRI antidepressants may also have beneficial effects on histadelic individuals, and anecdotal evidence supports this idea. As it stands, there is limited systematic research on these issues, and data are limited to clinical anecdotes and studies with small subject samples.
Acetyl-l-carnitine (ALC) is an ester derivative of the trimethylated amino acid, l-carnitine. ALC is synthesized in the human brain, liver, and kidney via the enzyme ALC-transferase. ALC is also available in the diet, in meat and dairy products. ALC facilitates uptake of acetyl CoA into the mitochondria during fatty acid oxidation, enhances acetylcholine production, and stimulates protein and membrane phospholipid synthesis (Indiveri et al., 2011). Several studies, including some double-blind, placebo-controlled trials, have shown that ALC may be of benefit in treating geriatric depression (Tempesta et al., 1987), attention deficit disorder in children (Sarris et al., 2011), and cognitive impairment associated with dementia (Hudson and Tabet, 2003) or alcoholism (Tempesta et al., 1990). Despite a number of published investigations suggesting beneficial effects of ALC in the psychiatric population, there are no known studies measuring serum levels of carnitine in depressed individuals. While such a carnitine-related mechanism of depression would not seem to suggest a clear link to SAMe, if a carnitine deficiency plays a causative role in the development of depression, such an investigation would provide new insights into mechanisms of depression and approaches to treatment.
Due to these considerations, the primary aim of this research was to first assess the efficacy of SAMe versus escitalopram and placebo in treating MDD via 12 weeks of randomized, double-blind treatment (at the Massachusetts General Hospital site). The results of the parent study (cf. Mischoulon et al., 2014) revealed no significant effects between groups across time, however there was a significant effect in favor of SAMe over placebo at weeks 8 and 10. A range of factors may account for this (highlighted in the Discussion section).
Our second aim was to analyze the relationship between histamine and carnitine levels and their response; and third, to determine if histamine or carnitine levels changed during the course of antidepressant treatment. We hypothesized that subjects with higher baseline levels of serum histamine or lower levels of carnitine would be more likely to improve with SAMe treatment compared to those with lower levels of histamine and higher levels of carnitine. We also predicted that SAMe treatment would be associated with lowering of serum histamine levels.
Section snippets
Overview and eligibility requirements
The data were provided from a clinical trial site (Massachusetts General Hospital: MGH) of a two-site parent study involving the acute 12-week controlled phase of a double-blind, placebo-controlled administration of SAMe versus escitalopram in 189 participants with MDD. This paper examines 144 subjects from the MGH site. The study was approved by the Partners Human Research Committee (IRB) and was registered on ClinicalTrials.Gov (NCT00101452).
The full methodology of the parent trial is
Results
One hundred forty four eligible participants (44% female, mean age 47.6±13.1) with diagnosed MDD underwent the washout screening phase. Fifty-four participants completed the study: SAMe (n=18), escitalopram (n=20), and placebo (n=16), with no significant difference in attrition rates between groups. Upon study completion102 participants meeting inclusion criteria had data available for analysis SAMe (n=32), escitalopram (n=35), and placebo (n=35). Seventy four percent (74%) of the sample
Discussion
Our results suggest that SAMe is significantly more effective than placebo in reducing depressed mood, while the SSRI comparator did not achieve this result. The effect size was moderate to large for SAMe indicating that a strong clinical effect occurred. This effect was maintained throughout the study, except that as the ANCOVA slope pattern depicts, the HAMD-17 scores rose slightly during the last two weeks for the SAMe group. In the escitalopram group, the ANCOVA slope revealed a steady
Role of funding source
The parent study was supported by Grant R01AT001638-01A1 to Dr. Maurizio Fava, from the National Institutes of Health (NIH) and the National Center for Complementary and Alternative Medicine (NCCAM).
Dr. Jerome Sarris was funded by a CR Roper Fellowship.
Dr. David Mischoulon was funded by a Grant from the Bowman Family Foundation.
Conflict of interest
Dr Sarris has received either presentation honoraria, travel support, clinical trial grants, book royalties from Integria Healthcare, MediHerb, Pfizer, Taki Mai, Pepsico, Bioceuticals & Blackmores, Soho-Flordis, Elsevier, HealthMasters, the National Health and Medical Research Council (NHMRC), CR Roper Fellowship. Dr Mischoulon has received research support from Nordic Naturals, Fisher Wallace, and Methylation Sciences, Inc. He has received speaking honoraria from Pamlab and from the MGH
Acknowledgments
Dr Jerome Sarris is funded by a CR Roper Fellowship.
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