human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Depression is one of the most disabling diseases , and causes a significant burden both to the individual and to society . WHO data suggests that depression causes 6 % of the burden of all diseases in Europe in terms of disability adjusted life years ( DALYs ) . Yet , the knowledge of the economic impact of depression has been relatively little research ed in Europe . AIMS OF THE STUDY The present study aims at estimating the total cost of depression  in Europe based on published epidemiologic and economic evidence . METHODS A model was developed to combine epidemiological and economic data on depression in Europe to estimate the cost . The model was populated with data collected from extensive literature review s of the epidemiology and economic burden of depression in Europe . The cost data was calculated as annual cost per patient , and epidemiologic data was reported as 12-month prevalence estimates . National and international statistics for the model were retrieved from the OECD and Eurostat data bases . The aggregated annual cost estimates were presented in Euro for 2004 . RESULTS In 28 countries with a population of 466 million , at least 21 million were affected by depression . The total annual cost of depression in Europe was estimated at Euro 118 billion in 2004 , which corresponds to a cost of Euro 253 per inhabitant . Direct costs alone totalled dollar 42 billion , comprised of outpatient care ( Euro 22 billion ) , drug cost ( Euro 9 billion ) and hospitalization ( Euro 10 billion ) . Indirect costs due to morbidity and mortality were estimated at Euro 76 billion . This makes depression the most costly brain disorder in Europe , accounting for 33 % of the total cost . The cost of depression corresponds to 1 % of the total economy of Europe ( GDP ) . DISCUSSION Our cost results are in good agreement with previous research findings . The cost estimates in the present study are based on model simulations for countries where no data was available . The predictability of our model is limited to the accuracy of the input data employed . As there is no earlier cost-of-illness study conducted on depression in Europe , it is , however , difficult to evaluate the validity of our results for individual countries and thus further research is needed . CONCLUSION The cost of depression poses a significant economic burden to European society . The simulation model employed shows good predictability of the cost of depression in Europe and is a novel approach to estimate the cost-of-illness in Europe . IMPLICATION S FOR HEALTH CARE PROVISION AND POLICIES : Health and social care policy and commissioning must be evidence -based . The empirical results from this study confirm previous findings , that depression is a major concern to the economic welfare in Europe which has consequences to both healthcare providers and policy makers . One important way to stop this explosion in cost is through increased research efforts in the field . Moreover , better detection , prevention , treatment and patient management are imperatives to reduce the burden of depression and its costs . Mental healthcare policies and better access to healthcare for mentally ill are other challenges to improve for Europe . IMPLICATION S FOR FURTHER RESEARCH This study has identified several research gaps which are of interest for future research . In order to better underst and the impact of depression to European society long-term prospect i ve epidemiology and cost-of-illness studies are needed . In particular data is lacking for Central European countries . On the basis of our findings , further economic evaluations of treatments for depression are necessary in order to ensure a cost-effective use of European healthcare budgets OBJECTIVE To assess the antidepressant efficacy of S-adenosyl methionine ( SAMe ) , a naturally occurring methyl donor , versus the selective serotonin reuptake inhibitor ( SSRI ) escitalopram and a placebo control ; and to determine whether serum histamine or carnitine levels modified treatment response . METHODS We examined a sub sample ( n=144 ) from one site of a two-site study of adults with diagnosed Major Depressive Disorder ( MDD ) , recruited from 4/13/05 to 12/22/09 , who consented to the additional blood draw for serum histamine and carnitine levels . After washout , eligible subjects were r and omized to SAMe ( 1600 - 3200mg/daily ) , escitalopram ( 10 - 20mg/daily ) , or matching placebo for 12 weeks of double-blind treatment ( titration at week 6 in non-response ) . RESULTS On the primary outcome of the Hamilton Depression Rating Scale ( HAMD-17 ) , a significant difference in improvement was observed between groups from baseline to week 12 ( p=0.039 ) . The effect size from baseline to endpoint was moderate to large for SAMe versus placebo ( d=0.74 ) . SAMe was superior to placebo from week 1 , and to escitalopram during weeks 2 , 4 , and 6 . No significant effect was found between escitalopram and placebo or SAMe  . Response rates ( HAMD-17≥50 % reduction ) at endpoint were 45 % , 31 % , and 26 % for SAMe , escitalopram , and placebo , respectively ; while remission rates ( HAM-D≤7 ) were 34 % for SAMe ( p=0.003 ) , 23 % for escitalopram ( p=0.023 ) , and 6 % for placebo . No correlation between baseline histamine level and reduction of HAMD-17 score was found for either the SAMe or escitalopram  groups . Baseline carnitine levels were also not found to moderate response to either treatment . LIMITATIONS While SAMe appears to be an effective antidepressant agent , the overall findings from the parent study ( which showed no significant difference between groups due to site differences ) must be taken into consideration . CONCLUSIONS These preliminary results provide encouraging evidence for the use of SAMe in the treatment of MDD . Histamine and carnitine serum level may not necessarily moderate response to SAMe OBJECTIVE To characterize the impact of S-adenosyl methionine ( SAMe ) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe , S-adenosyl homocysteine ( SAH ) , total homocysteine ( tHCY ) , methionine ( MET ) , and 5-methyltetrahydrofolate ( 5-MTHF ) in 35 of 73 patients from a 6-week r and omized double-blind , placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder ( MDD ) , published in 2010 . METHOD Subjects were r and omized from June 4 , 2004 , until August 8 , 2008 , to adjunctive placebo or SAMe 800 - 1600 mg/d for 6 weeks . Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm ( by paired t test ) and between treatment arms ( by independent sample s t test ) . Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate . Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels , examined by linear regression ( for change in Hamilton Depression Rating Scale scores ) and logistic regression ( for response or remission ) . RESULTS We found significant differences in pretreatment plasma levels of tHCY ( P = .03 ) between the SAMe and placebo arms . Following 6 weeks of treatment , plasma SAMe ( P = .002 ) and SAH ( P < .0001 ) levels increased significantly in the SAMe arm ; no intermediates in the placebo group changed significantly . Posttreatment plasma SAMe ( P = .0035 ) , SAH ( P < .0001 ) , and tHCY ( P = .0016 ) levels differed significantly between the SAMe and placebo groups . No significant associations were found between plasma intermediate levels and clinical improvement , response , or remission . CONCLUSIONS Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects , the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected . Our findings , however , have some significant limitations and should be interpreted with caution . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00093847 Cerebrospinal fluid ( CSF ) S-adenosylmethionine ( SAM ) levels were significantly lower in severely depressed patients than in a neurological control group . The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM , indicating that it crosses the blood-brain barrier in humans . These observations provide a rational basis for the antidepressant effect of SAM , which has been confirmed in several countries . CSF SAM levels were low in a group of patients with Alzheimer 's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment Background This study reports on clinical data from an 8-week open-label study of 20 HIV-seropositive individuals , diagnosed with Major Depressive Disorder ( DSM-IV ) , who were treated with SAM-e ( S-Adenosylmethionine ) . SAM-e may be a treatment alternative for the management of depression in a population reluctant to add another " pill " or another set of related side effects to an already complex highly active antiretroviral therapy ( HAART ) regimen . Methods The Hamilton Rating Scale for Depression ( HAM-D ) and the Beck Depression Inventory ( BDI ) were used to assess depressive symptomatology from 1,2,4,6 and 8 weeks after initiation of treatment with SAM-e . Results Data show a significant acute reduction in depressive symptomatology , as measured by both the HAM-D and the BDI instruments . Conclusions SAM-e has a rapid effect evident as soon as week 1 ( p < .001 ) , with progressive decreases in depression symptom rating scores throughout the 8 week study We evaluated the predictive value of the thyrotropin ( TSH ) response to thyrotropin‐releasing hormone ( TRH ) in 32 depressed out patients completing a double‐blind placebo‐controlled trial of s‐adenosyl‐l‐methionine ( SAMe )  , which failed to show any significant difference between SAMe and placebo . Treatment response was defined as the change in Hamilton Rating Scale for Depression ( HRSD‐24 ) score between baseline and the end of the six‐week trial . Subjects with TSH response outside the normal range ( 7–25 uU/ml ) had a significantly greater response than patients with a normal response . There was also a significant correlation between absolute deviations from the mean TSH response ( 16 uU/ml ) and changes in HRSD‐24 scores S-adenosyl-L-methionine ( SAMe ) is a naturally occurring substance which is a major source of methyl groups in the brain and has been found in previous studies to be an effective antidepressant . The aim of this study was to assess the efficacy of oral SAMe in the treatment of depressed postmenopausal women in a 30-day double-blind placebo-controlled r and omized trial . During the course of the study , 80 women , between the ages of 45 and 59 , who were diagnosed as having DSM-III-R major depressive disorder or dysthymia between 6 and 36 months following either natural menopause or hysterectomy , underwent 1 week of single-blind placebo washout , followed by 30 days of double-blind treatment with either SAMe 1,600 mg/day or placebo . There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study . Side effects were mild and transient BACKGROUND S-Adenosyl-L-methionine ( SAMe ) , a natural compound , is the most important methyl donor in the central nervous system . In several clinical trials , SAMe showed antidepressant activity . OBJECTIVE Two multicenter studies were conducted in patients with a diagnosis of major depressive episode [ baseline score on the 21-item Hamilton Depression Rating Scale ( HAM-D ) > or=18 ] to confirm the efficacy and safety of SAMe in the treatment of major depression . In the first study ( MC3 ) , 1600 mg SAMe/d was given orally ; whereas , in the second study ( MC4 ) , 400 mg SAMe/d was given intramuscularly . In both studies , the effects of SAMe were compared with those of 150 mg imipramine/d given orally in a double-blind design . DESIGN In  MC3 , 143 patients received oral SAMe and 138 patients received imipramine for 6 wk . In  MC4 , 147 patients received SAMe intramuscularly and 148 patients received imipramine for 4 wk . In both studies the 2 main efficacy measures were the final HAM-D score and the percentage of responders to Clinical Global Impression at the endpoint . Secondary efficacy measures were the endpoint Montgomery-Asberg Depression Rating Scale scores and the percentage of responders , responders being those patients showing a decrease in HAM-D score of > or=50 % from baseline . RESULTS In both studies , the results of SAMe and imipramine treatment did not differ significantly for any efficacy measure . However , significantly fewer adverse events were observed in the patients treated with SAMe . CONCLUSIONS The antidepressive efficacy of 1600 mg SAMe/d orally and 400 mg SAMe/d intramuscularly is comparable with that of 150 m 
    Output:
    
agent
SAMe was not different from placebo and established antidepressants .
The exception was that compared to imipramine , fewer participants experienced troublesome adverse effects when treated with parenteral SAMe .
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Depression is one of the most disabling diseases , and causes a significant burden both to the individual and to society . WHO data suggests that depression causes 6 % of the burden of all diseases in Europe in terms of disability adjusted life years ( DALYs ) . Yet , the knowledge of the economic impact of depression has been relatively little research ed in Europe . AIMS OF THE STUDY The present study aims at estimating the total cost of depression  in Europe based on published epidemiologic and economic evidence . METHODS A model was developed to combine epidemiological and economic data on depression in Europe to estimate the cost . The model was populated with data collected from extensive literature review s of the epidemiology and economic burden of depression in Europe . The cost data was calculated as annual cost per patient , and epidemiologic data was reported as 12-month prevalence estimates . National and international statistics for the model were retrieved from the OECD and Eurostat data bases . The aggregated annual cost estimates were presented in Euro for 2004 . RESULTS In 28 countries with a population of 466 million , at least 21 million were affected by depression . The total annual cost of depression in Europe was estimated at Euro 118 billion in 2004 , which corresponds to a cost of Euro 253 per inhabitant . Direct costs alone totalled dollar 42 billion , comprised of outpatient care ( Euro 22 billion ) , drug cost ( Euro 9 billion ) and hospitalization ( Euro 10 billion ) . Indirect costs due to morbidity and mortality were estimated at Euro 76 billion . This makes depression the most costly brain disorder in Europe , accounting for 33 % of the total cost . The cost of depression corresponds to 1 % of the total economy of Europe ( GDP ) . DISCUSSION Our cost results are in good agreement with previous research findings . The cost estimates in the present study are based on model simulations for countries where no data was available . The predictability of our model is limited to the accuracy of the input data employed . As there is no earlier cost-of-illness study conducted on depression in Europe , it is , however , difficult to evaluate the validity of our results for individual countries and thus further research is needed . CONCLUSION The cost of depression poses a significant economic burden to European society . The simulation model employed shows good predictability of the cost of depression in Europe and is a novel approach to estimate the cost-of-illness in Europe . IMPLICATION S FOR HEALTH CARE PROVISION AND POLICIES : Health and social care policy and commissioning must be evidence -based . The empirical results from this study confirm previous findings , that depression is a major concern to the economic welfare in Europe which has consequences to both healthcare providers and policy makers . One important way to stop this explosion in cost is through increased research efforts in the field . Moreover , better detection , prevention , treatment and patient management are imperatives to reduce the burden of depression and its costs . Mental healthcare policies and better access to healthcare for mentally ill are other challenges to improve for Europe . IMPLICATION S FOR FURTHER RESEARCH This study has identified several research gaps which are of interest for future research . In order to better underst and the impact of depression to European society long-term prospect i ve epidemiology and cost-of-illness studies are needed . In particular data is lacking for Central European countries . On the basis of our findings , further economic evaluations of treatments for depression are necessary in order to ensure a cost-effective use of European healthcare budgets OBJECTIVE To assess the antidepressant efficacy of S-adenosyl methionine ( SAMe ) , a naturally occurring methyl donor , versus the selective serotonin reuptake inhibitor ( SSRI ) escitalopram and a placebo control ; and to determine whether serum histamine or carnitine levels modified treatment response . METHODS We examined a sub sample ( n=144 ) from one site of a two-site study of adults with diagnosed Major Depressive Disorder ( MDD ) , recruited from 4/13/05 to 12/22/09 , who consented to the additional blood draw for serum histamine and carnitine levels . After washout , eligible subjects were r and omized to SAMe ( 1600 - 3200mg/daily ) , escitalopram ( 10 - 20mg/daily ) , or matching placebo for 12 weeks of double-blind treatment ( titration at week 6 in non-response ) . RESULTS On the primary outcome of the Hamilton Depression Rating Scale ( HAMD-17 ) , a significant difference in improvement was observed between groups from baseline to week 12 ( p=0.039 ) . The effect size from baseline to endpoint was moderate to large for SAMe versus placebo ( d=0.74 ) . SAMe was superior to placebo from week 1 , and to escitalopram during weeks 2 , 4 , and 6 . No significant effect was found between escitalopram and placebo or SAMe  . Response rates ( HAMD-17≥50 % reduction ) at endpoint were 45 % , 31 % , and 26 % for SAMe , escitalopram , and placebo , respectively ; while remission rates ( HAM-D≤7 ) were 34 % for SAMe ( p=0.003 ) , 23 % for escitalopram ( p=0.023 ) , and 6 % for placebo . No correlation between baseline histamine level and reduction of HAMD-17 score was found for either the SAMe or escitalopram  groups . Baseline carnitine levels were also not found to moderate response to either treatment . LIMITATIONS While SAMe appears to be an effective antidepressant agent , the overall findings from the parent study ( which showed no significant difference between groups due to site differences ) must be taken into consideration . CONCLUSIONS These preliminary results provide encouraging evidence for the use of SAMe in the treatment of MDD . Histamine and carnitine serum level may not necessarily moderate response to SAMe OBJECTIVE To characterize the impact of S-adenosyl methionine ( SAMe ) on homocysteine and potential risk of adverse cardiovascular effects by examining plasma levels of SAMe , S-adenosyl homocysteine ( SAH ) , total homocysteine ( tHCY ) , methionine ( MET ) , and 5-methyltetrahydrofolate ( 5-MTHF ) in 35 of 73 patients from a 6-week r and omized double-blind , placebo-controlled trial of SAMe augmentation in serotonin reuptake inhibitor partial responders with DSM-IV major depressive disorder ( MDD ) , published in 2010 . METHOD Subjects were r and omized from June 4 , 2004 , until August 8 , 2008 , to adjunctive placebo or SAMe 800 - 1600 mg/d for 6 weeks . Primary outcome measures included changes in one-carbon cycle intermediates within each treatment arm ( by paired t test ) and between treatment arms ( by independent sample s t test ) . Univariate analysis of variance and Fisher Protected Least Significant Difference were carried out to compare posttreatment levels of each one-carbon cycle intermediate . Secondary outcome measures included associations between clinical improvement and change in plasma intermediate levels , examined by linear regression ( for change in Hamilton Depression Rating Scale scores ) and logistic regression ( for response or remission ) . RESULTS We found significant differences in pretreatment plasma levels of tHCY ( P = .03 ) between the SAMe and placebo arms . Following 6 weeks of treatment , plasma SAMe ( P = .002 ) and SAH ( P < .0001 ) levels increased significantly in the SAMe arm ; no intermediates in the placebo group changed significantly . Posttreatment plasma SAMe ( P = .0035 ) , SAH ( P < .0001 ) , and tHCY ( P = .0016 ) levels differed significantly between the SAMe and placebo groups . No significant associations were found between plasma intermediate levels and clinical improvement , response , or remission . CONCLUSIONS Despite concerns about the impact that SAMe therapy may have on homocysteine levels and risk of adverse cardiovascular effects , the lack of significant increase in tHCY levels after treatment suggests that no toxic effects from SAMe should be expected . Our findings , however , have some significant limitations and should be interpreted with caution . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00093847 Cerebrospinal fluid ( CSF ) S-adenosylmethionine ( SAM ) levels were significantly lower in severely depressed patients than in a neurological control group . The administration of SAM either intravenously or orally is associated with a significant rise of CSF SAM , indicating that it crosses the blood-brain barrier in humans . These observations provide a rational basis for the antidepressant effect of SAM , which has been confirmed in several countries . CSF SAM levels were low in a group of patients with Alzheimer 's dementia suggesting a possible disturbance of methylation in such patients and the need for trials of SAM treatment Background This study reports on clinical data from an 8-week open-label study of 20 HIV-seropositive individuals , diagnosed with Major Depressive Disorder ( DSM-IV ) , who were treated with SAM-e ( S-Adenosylmethionine ) . SAM-e may be a treatment alternative for the management of depression in a population reluctant to add another " pill " or another set of related side effects to an already complex highly active antiretroviral therapy ( HAART ) regimen . Methods The Hamilton Rating Scale for Depression ( HAM-D ) and the Beck Depression Inventory ( BDI ) were used to assess depressive symptomatology from 1,2,4,6 and 8 weeks after initiation of treatment with SAM-e . Results Data show a significant acute reduction in depressive symptomatology , as measured by both the HAM-D and the BDI instruments . Conclusions SAM-e has a rapid effect evident as soon as week 1 ( p < .001 ) , with progressive decreases in depression symptom rating scores throughout the 8 week study We evaluated the predictive value of the thyrotropin ( TSH ) response to thyrotropin‐releasing hormone ( TRH ) in 32 depressed out patients completing a double‐blind placebo‐controlled trial of s‐adenosyl‐l‐methionine ( SAMe )  , which failed to show any significant difference between SAMe and placebo . Treatment response was defined as the change in Hamilton Rating Scale for Depression ( HRSD‐24 ) score between baseline and the end of the six‐week trial . Subjects with TSH response outside the normal range ( 7–25 uU/ml ) had a significantly greater response than patients with a normal response . There was also a significant correlation between absolute deviations from the mean TSH response ( 16 uU/ml ) and changes in HRSD‐24 scores S-adenosyl-L-methionine ( SAMe ) is a naturally occurring substance which is a major source of methyl groups in the brain and has been found in previous studies to be an effective antidepressant . The aim of this study was to assess the efficacy of oral SAMe in the treatment of depressed postmenopausal women in a 30-day double-blind placebo-controlled r and omized trial . During the course of the study , 80 women , between the ages of 45 and 59 , who were diagnosed as having DSM-III-R major depressive disorder or dysthymia between 6 and 36 months following either natural menopause or hysterectomy , underwent 1 week of single-blind placebo washout , followed by 30 days of double-blind treatment with either SAMe 1,600 mg/day or placebo . There was a significantly greater improvement in depressive symptoms in the group treated with SAMe compared to the placebo group from day 10 of the study . Side effects were mild and transient BACKGROUND S-Adenosyl-L-methionine ( SAMe ) , a natural compound , is the most important methyl donor in the central nervous system . In several clinical trials , SAMe showed antidepressant activity . OBJECTIVE Two multicenter studies were conducted in patients with a diagnosis of major depressive episode [ baseline score on the 21-item Hamilton Depression Rating Scale ( HAM-D ) > or=18 ] to confirm the efficacy and safety of SAMe in the treatment of major depression . In the first study ( MC3 ) , 1600 mg SAMe/d was given orally ; whereas , in the second study ( MC4 ) , 400 mg SAMe/d was given intramuscularly . In both studies , the effects of SAMe were compared with those of 150 mg imipramine/d given orally in a double-blind design . DESIGN In  MC3 , 143 patients received oral SAMe and 138 patients received imipramine for 6 wk . In  MC4 , 147 patients received SAMe intramuscularly and 148 patients received imipramine for 4 wk . In both studies the 2 main efficacy measures were the final HAM-D score and the percentage of responders to Clinical Global Impression at the endpoint . Secondary efficacy measures were the endpoint Montgomery-Asberg Depression Rating Scale scores and the percentage of responders , responders being those patients showing a decrease in HAM-D score of > or=50 % from baseline . RESULTS In both studies , the results of SAMe and imipramine treatment did not differ significantly for any efficacy measure . However , significantly fewer adverse events were observed in the patients treated with SAMe . CONCLUSIONS The antidepressive efficacy of 1600 mg SAMe/d orally and 400 mg SAMe/d intramuscularly is comparable with that of 150 m 
    Output:
    