according to  the world health report 2001  by the world health organization , approximately one in ten persons suffer from depression globally , and depression is expected to become the second most common disease after coronary heart disease in 2020 . the incidence of depression in the people s republic of china is estimated at 5%6% of the population1 compared to 15.4% in the us2 and 27% in european countries.3 the total number of depression patients in the people s republic of china has reached 90 million1 and continues to rise , compromising the health of the general population . depression has a long treatment cycle period , slow efficacy of medications , and high recurrence rate . fluoxetine , paroxetine , sertraline , citalopram , escitalopram , and fluvoxamine are the most commonly used selective serotonin reuptake inhibitors ( ssris ) for treatment of major depression . however , these antidepressants may cause multiple side effects , such as nausea , insomnia , and sexual dysfunction.4 thirty - eight percent of patients with long - term use of ssris have experienced at least one side effect , with sexual dysfunction , sleepiness , and weight gain being the most common.5 well - defined extracts from st john s wort ( hypericum perforatum ) , namely , st john s wort extract ( neurostan ) , have been used to treat depression for more than a 100 years in germany . significant efficacy and safety have been demonstrated in animal studies and clinical trials.6,7 st john s wort has better antidepressant efficacy than placebo810 and lower rates of side effects than conventional antidepressants.11,12 the use of st john s wort extract for patients with depression , however , remains somewhat controversial , since some studies showed no significant difference in efficacy and safety between st john s wort extract and conventional ssris.1115 given that depression often requires rapid , timely , and prolonged treatment , we should consider not only the effectiveness but also safety of the treatment . therefore , based on the meta - analysis by rahimi et al,16 which covers literature from 1966 to june 2008 , we collected published randomized , controlled clinical trials comparing the efficacy and safety of st john s wort extract and ssris from june 2008 to april 2015 . in addition , we included similar studies that have been published since 1966 in the people s republic of china to conduct a comprehensive and objective update on the use of st john s wort extract as an alternative to ssris . neurostan  and  fluoxetine  or  paroxetine  or  citalopram  or  sertraline  or  escitalopram  or  fluvoxamine  and  depression . pubmed , cochrane central register of controlled trials , and ovid technologies were searched from june 2008 to april 2015 , and china biology medicine disc , wanfang data , and china national knowledge infrastructure were searched from 1966 to april 2015 . we searched for studies of treatment of depression with st john s wort extract with no language restriction . all studies were required to meet the following inclusion criteria : 1 ) randomized controlled trials , 2 ) depressive patients , 3 ) at least 4 weeks of treatment , 4 ) ssri - controlled , 5 ) available efficacy or safety indicators , and 6 ) outcome measures for depression or clinical diagnosis . exclusion criteria were as follows : 1 ) lack of data on efficacy and safety , 2 ) combination with other antidepressants , and 3 ) single - blind and uncontrolled trials . data from selected studies were extracted in tabular form , including basic information on the study , study design , study time , intervention measures , and specific outcomes . the primary outcome measure for treatment efficacy and safety was change in total hamilton rating scale for depression ( hamd ) score between baseline and end point . responder rates ( reduction in hamd score > 50% ) , remission rate ( reduction in hamd score > 75% ) , mean reduction in hamd score , the incidence of adverse events , total withdrawal rate , and withdrawals due to adverse events were the key outcomes of interest . some of the data in this study were not directly usable for statistical analysis , and therefore , converted into a form available for analysis . the main formulas used were 1 ) calculation of mean and standard deviation ( sd ) for change according to the known mean and sd before and after treatment : mean ( b  a ) = mean ( b ) ( a ) , variance ( b  a ) = variance ( b ) + variance ( a ) , taking the square root to obtain sd : ( b  a ) and 2 ) calculation of sd : ( cimax  cimin)/(1.962 ) by using the confidence intervals . all included studies were analyzed using stata / se ( 11.2 ) ( statacorp lp , college station , tx , usa ) . for each meta - analysis , heterogeneity of treatment effects was tested before the data were pooled ; if p>0.05 or i<50% , we considered the data to be homogeneous and used a fixed - effects model . otherwise , we applied a random - effects model . relative risk ( rr ) and 95% confidence intervals ( 95% ci ) were calculated , and effect size ( weighted mean difference ) meta - analysis was performed . the event rate in the experimental ( intervention ) group against the event rate in the control group was calculated using the chi - square test , and the results were expressed as an odds ratio ( or ) and p - values . neurostan  and  fluoxetine  or  paroxetine  or  citalopram  or  sertraline  or  escitalopram  or  fluvoxamine  and  depression . pubmed , cochrane central register of controlled trials , and ovid technologies were searched from june 2008 to april 2015 , and china biology medicine disc , wanfang data , and china national knowledge infrastructure were searched from 1966 to april 2015 . we searched for studies of treatment of depression with st john s wort extract with no language restriction . all studies were required to meet the following inclusion criteria : 1 ) randomized controlled trials , 2 ) depressive patients , 3 ) at least 4 weeks of treatment , 4 ) ssri - controlled , 5 ) available efficacy or safety indicators , and 6 ) outcome measures for depression or clinical diagnosis . exclusion criteria were as follows : 1 ) lack of data on efficacy and safety , 2 ) combination with other antidepressants , and 3 ) single - blind and uncontrolled trials . data from selected studies were extracted in tabular form , including basic information on the study , study design , study time , intervention measures , and specific outcomes . the primary outcome measure for treatment efficacy and safety was change in total hamilton rating scale for depression ( hamd ) score between baseline and end point . responder rates ( reduction in hamd score > 50% ) , remission rate ( reduction in hamd score > 75% ) , mean reduction in hamd score , the incidence of adverse events , total withdrawal rate , and withdrawals due to adverse events were the key outcomes of interest . some of the data in this study were not directly usable for statistical analysis , and therefore , converted into a form available for analysis . the main formulas used were 1 ) calculation of mean and standard deviation ( sd ) for change according to the known mean and sd before and after treatment : mean ( b  a ) = mean ( b )  ( a ) , variance ( b  a ) = variance ( b ) + variance ( a ) , taking the square root to obtain sd : ( b  a ) and 2 ) calculation of sd : ( cimax  cimin)/(1.962 ) by using the confidence intervals . all included studies were analyzed using stata / se ( 11.2 ) ( statacorp lp , college station , tx , usa ) . for each meta - analysis , heterogeneity of treatment effects was tested before the data were pooled ; if p>0.05 or i<50% , we considered the data to be homogeneous and used a fixed - effects model . otherwise , we applied a random - effects model . relative risk ( rr ) and 95% confidence intervals ( 95% ci ) were calculated , and effect size ( weighted mean difference ) meta - analysis was performed . the event rate in the experimental ( intervention ) group against the event rate in the control group was calculated using the chi - square test , and the results were expressed as an odds ratio ( or ) and p - values . a total of 27 articles were retrieved.1115,1724 the basic data of all studies are shown in table 1 . a total of 3,126 patients were included in the analysis , with 1,177 patients from the people s republic of china . summary rr for all included studies for clinical response was 1.02 ( 95% ci : 0.96 , 1.09 , p=0.51 , figure 1 ) . furthermore , the combined summary rr of all studies for remission by st john s wort extract versus ssris therapy was 1.07 ( 95% ci : 0.94 , 1.22 , p=0.308 , figure 2 ) . effect size ( standard mean difference ) for mean reduction in hamd score from baseline with st john s wort extract versus ssris therapy among all the studies was 0.06 ( 95% ci : 0.13 , 0.02 , p=0.15 , figure 3 ) . the number of patients reporting adverse events and withdrawal due to adverse events were evaluated in 19 and 12 trials , respectively . the summary rr for adverse events of st john s wort extract versus ssri therapy among all included trials was 0.77 ( 95% ci : 0.70 , 0.84 , p=0.00 ) ( figure 4 ) . twelve trials investigated withdrawals and withdrawal due to adverse events of st john s wort extract and ssri therapy . the total withdrawal rate and withdrawal rate due to adverse events were 18.2% ( 167/916 ) and 4.1% ( 38/916 ) in the st john s wort extract group , and 20.3% ( 183/901 ) and 6.7% ( 61/901 ) in the ssri group , respectively . there was no significant difference in the total withdrawal rate of the two groups ( chi - square test ; or = 0.88 , 95% ci : 0.69 , 1.11 , p=0.28 ) . withdrawal due to adverse events in the st john s wort extract group was significantly less than that in the ssri group ( or = 0.60 , 95% ci : 0.39 , 0.90 , p=0.02 ) . we did not observe a skewed distribution and the data substantially met a normal distribution , and the publication bias was also small . there was no significant difference between the statistical results before and after each exclusion , indicating that the study was stable and reliable . summary rr for all included studies for clinical response was 1.02 ( 95% ci : 0.96 , 1.09 , p=0.51 , figure 1 ) . furthermore , the combined summary rr of all studies for remission by st john s wort extract versus ssris therapy was 1.07 ( 95% ci : 0.94 , 1.22 , p=0.308 , figure 2 ) . effect size ( standard mean difference ) for mean reduction in hamd score from baseline with st john s wort extract versus ssris therapy among all the studies was 0.06 ( 95% ci : 0.13 , 0.02 , p=0.15 , figure 3 ) . the number of patients reporting adverse events and withdrawal due to adverse events were evaluated in 19 and 12 trials , respectively . the summary rr for adverse events of st john s wort extract versus ssri therapy among all included trials was 0.77 ( 95% ci : 0.70 , 0.84 , p=0.00 ) ( figure 4 ) . twelve trials investigated withdrawals and withdrawal due to adverse events of st john s wort extract and ssri therapy . the total withdrawal rate and withdrawal rate due to adverse events were 18.2% ( 167/916 ) and 4.1% ( 38/916 ) in the st john s wort extract group , and 20.3% ( 183/901 ) and 6.7% ( 61/901 ) in the ssri group , respectively . there was no significant difference in the total withdrawal rate of the two groups ( chi - square test ; or = 0.88 , 95% ci : 0.69 , 1.11 , p=0.28 ) . withdrawal due to adverse events in the st john s wort extract group was significantly less than that in the ssri group ( or = 0.60 , 95% ci : 0.39 , 0.90 , p=0.02 ) . we did not observe a skewed distribution and the data substantially met a normal distribution , and the publication bias was also small . there was no significant difference between the statistical results before and after each exclusion , indicating that the study was stable and reliable . although st john s wort extract has been used to treat depression for > 100 years and its efficacy810 and safety11,12 have been proven in several clinical studies , its use in depression still remains somewhat controversial . a meta - analysis by rahimi et al16 of 13 eligible randomized , placebo - controlled clinical trials published between 1966 and 2008 showed that st john s wort extract was comparable to ssris in efficacy and safety . our current meta - analysis included additional studies as of 2008 with a total of 27 eligible studies and 3,126 depression patients . we found that consistent with the findings of rahimi et al,16 st john s wort extract was comparable to ssris in efficacy , including clinical response , remission , and mean reduction in hamd score . unlike the study by rahimi et al,16 we further demonstrated that st john s wort extract had a lower incidence of adverse events than ssris . these findings indicate that , compared to ssris , st john s wort extract is equally effective , but has superior safety in the management of depression patients . st john s wort extract is currently the only pure plant antidepressant and is especially suitable for mild - to - moderate depression . it competitively inhibits absorption of serotonin , noradrenaline , and dopamine ; it also downregulates presynaptic membrane - adrenergic receptor density and reduces binding of neurotransmitters to presynaptic membrane - adrenergic receptors , thereby increasing their concentrations in the synaptic cleft , mimicking the effect of antidepressants.25,26 studies have shown that st john s wort extract is superior to placebo810 and comparable to ssris27 in efficacy . st john s wort causes mild adverse effects such as occasional dry mouth and constipation , and it causes no memory impairment , an apparent advantage for older patients.28 our study demonstrates significantly lower rates of adverse events in depression patients receiving st john s wort extract versus ssris , and consistent with the study by rahimi et al,16 markedly lower rates of withdrawal due to adverse events . one limitation of the current meta - analysis is the lack of data on treatment of adolescents with depression . a small number of studies have shown that st john s wort extract is superior to placebo in treating teenagers with moderate and severe depression;29,30 however , a definite conclusion awaits the results of randomized controlled trials involving a larger population of adolescents with depression . depression is a chronic disease requiring long - term medication therapy , incurring a financial burden on the patients . it is also important to investigate cost - effectiveness of st john s wort extract versus ssris , which was not addressed in our meta - analysis . solomon et al31 investigated the economic cost of st john s wort extract for mild - to - moderate depression using markov model and found that st john s wort extract markedly reduced medication costs compared with ssris . although st john s wort has been used as a herbal remedy for depression for many years , especially in germany and other european countries , its efficacy is still controversial . our meta - analysis analyzed 27 studies and 3,126 depression patients and so far represents the most comprehensive analysis of clinical studies on st john s wort for depression . although this study did not explore neurobiological mechanisms of st john s wort , our results are consistent with the hypothesis that st john s wort is an effective therapy for depression . furthermore , our analysis demonstrates that in the treatment of depression , especially mild - to - moderate depression , st john s wort extract has comparable efficacy to ssris , while the rate of adverse events and withdrawals is significantly lower than that of traditional ssris . given the low cost of treatment with st john s wort extract versus ssris , its significant efficacy , and good safety profile , st john s wort extract may be a preferred therapeutic choice in the management of depression .
objectivethe aim of the study was to investigate the efficacy and safety of st john s wort extract and selective serotonin reuptake inhibitors ( ssris ) in the treatment of depression.methodsdatabases were searched for studies comparing efficacy and/or safety of st john s wort extract with ssris in depression from 1966 to april 2015 . 
 stata software was used for statistical analysis.resultstwenty-seven studies met the study entry criteria . 
 a total of 3,126 patients with depression were included . 
 st john s wort extract did not differ from ssris in clinical response , remission , and mean reduction in hamilton rating scale for depression score . 
 st john s wort extract had a significantly lower rate of adverse events compared to ssris ( summary relative risk : 0.77 ; 95% confidence interval : 0.70 , 0.84 , p=0.00 ) and had fewer withdrawals due to adverse events . 
 st john s wort extract had superior safety in the management of patients with depression.conclusionboth st john s wort extract and ssris are effective in treating mild - to - moderate depression . 
 st john s wort extract is safer than ssris .