Abstract
INTRODUCTION: A boxed-warning in antidepressant labeling
now informs prescribers of the potential for treatmentemergent
suicidality to occur. Consequently, alternative
“natural” antidepressant therapies widely viewed to be devoid
of this risk, such as St. John’s wort (SJW) and s-adenosyl
methionine (SAM-e), may experience a resurgence in
popularity and expansion of use beyond mild forms of
depressive illness. The purpose of this article is to critically
assess whether the clinical evidence supports the use of SJW
and SAM-e as alternatives to conventional antidepressants in
the treatment of major depressive disorder (MDD). In addition,
this article evaluates whether the behavioral adverse event
pro!les of SJW and SAM-e suggest an increased risk for
suicidality, like their conventional counterparts. METHODS: A
comprehensive literature review was performed (Jan
1975-July 2010) to identify all English language reports of
placebo-controlled studies of SJW and SAM-e conducted for
psychiatric indications. MDD studies were categorized as
“positive” or “negative” based on statistical superiority to
placebo on prospectively-de!ned, primary, clinician-rated
e"cacy parameters (e.g., change in Hamilton Depression
scores [HAM-D] or Montgomery-Asberg Depression Rating
Scale [MADRS] total). Treatment e#ect size (Cohen’s d) was
also calculated in each case to assess the clinical relevance of
the !ndings. Behavioral-related adverse events were
summarized by treatment. RESULTS: Ten of 14 (71%) SJW
studies in mild-to-moderate MDD were positive. The mean
and median e#ect sizes for HAM-D change in those studies
were 0.64 and 0.48, respectively, indicative of a moderatelylarge
treatment e#ect. In the few studies that included
patients with severe symptoms, however, or which evaluated
long-term maintenance of e#ect, SJW did not di#erentiate
from placebo. The majority of SAM-e studies in MDD were also
positive (8/14, 57%); however, most were methodologically
$awed to some extent. Based on the magnitude of the
treatment-e#ect size in a number of positive studies, SJW
appears to be useful for the short-term treatment of
mild-to-moderate depressive illness in adults. Existing data do
not support the use of SJW in more severely depressed
individuals. The SAM-e clinical data also are strongly
suggestive of antidepressant e"cacy; however, until more
rigorously generated data become available it is not possible
to reach a more de!nitive conclusion. There are no long-term
treatment data that convincingly demonstrate long-term
maintenance of e#ect for either product. The reviewed studies
did not reveal evidence of treatment-emergent suicidality,
suggesting that this risk for either product is low. However, the
studies examined were not prospectively designed to detect
such events and therefore were likely unable to reliably assess
this risk.
(Altern Med Rev 2011;16(1):17-39)
AbstractINTRODUCTION: A boxed-warning in antidepressant labelingnow informs prescribers of the potential for treatmentemergentsuicidality to occur. Consequently, alternative“natural” antidepressant therapies widely viewed to be devoidof this risk, such as St. John’s wort (SJW) and s-adenosylmethionine (SAM-e), may experience a resurgence inpopularity and expansion of use beyond mild forms ofdepressive illness. The purpose of this article is to criticallyassess whether the clinical evidence supports the use of SJWand SAM-e as alternatives to conventional antidepressants inthe treatment of major depressive disorder (MDD). In addition,this article evaluates whether the behavioral adverse eventpro!les of SJW and SAM-e suggest an increased risk forsuicidality, like their conventional counterparts. METHODS: Acomprehensive literature review was performed (Jan1975-July 2010) to identify all English language reports ofplacebo-controlled studies of SJW and SAM-e conducted forpsychiatric indications. MDD studies were categorized as“positive” or “negative” based on statistical superiority toplacebo on prospectively-de!ned, primary, clinician-ratede"cacy parameters (e.g., change in Hamilton Depressionscores [HAM-D] or Montgomery-Asberg Depression RatingScale [MADRS] total). Treatment e#ect size (Cohen’s d) wasalso calculated in each case to assess the clinical relevance ofthe !ndings. Behavioral-related adverse events weresummarized by treatment. RESULTS: Ten of 14 (71%) SJWstudies in mild-to-moderate MDD were positive. The meanand median e#ect sizes for HAM-D change in those studieswere 0.64 and 0.48, respectively, indicative of a moderatelylargetreatment e#ect. In the few studies that includedpatients with severe symptoms, however, or which evaluatedlong-term maintenance of e#ect, SJW did not di#erentiatefrom placebo. The majority of SAM-e studies in MDD were alsopositive (8/14, 57%); however, most were methodologically$awed to some extent. Based on the magnitude of thetreatment-e#ect size in a number of positive studies, SJWappears to be useful for the short-term treatment ofmild-to-moderate depressive illness in adults. Existing data donot support the use of SJW in more severely depressedindividuals. The SAM-e clinical data also are stronglysuggestive of antidepressant e"cacy; however, until morerigorously generated data become available it is not possibleto reach a more de!nitive conclusion. There are no long-termtreatment data that convincingly demonstrate long-termmaintenance of e#ect for either product. The reviewed studiesdid not reveal evidence of treatment-emergent suicidality,suggesting that this risk for either product is low. However, thestudies examined were not prospectively designed to detectsuch events and therefore were likely unable to reliably assessthis risk.(Altern Med Rev 2011;16(1):17-39)
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