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: Lithium augmentation is one of the best studied strategies for resistant depression . The lithium dosage usually given is around 900 mg/day and plasma level is maintained in the range of 0.5 - 0.8 mEq/L. However , the administration of lithium in this dosage necessitates monitoring of plasma concentration and increases the risk of toxicity and side effects . Since it has been shown that low lithium levels increase serotonin turnover and enhance serotonin neurotransmission , we thought it of interest to assess the efficacy of low dosage lithium augmentation for patients with resistant depression . Fifty one patients suffering from severe unipolar or bipolar depression who had failed to respond to treatment with venlafaxine 300 - 375 mg/day were included in the study and treated as out patients . Patients had previously been exposed to unsuccessful treatment with various antidepressants , mostly SSRIs . After a washout period for previously administered antidepressants of one week , the dosage of venlafaxine was rapidly titrated to 300 or 375 mg/day , corresponding to about 5 mg/kg . The dose remained stable during the next six weeks . Additional antipsychotic medication was allowed to treat psychotic symptoms . Forty seven severely depressed patients who failed to respond to 300 - 375 mg/day venlafaxine  were , in addition , given lithium carbonate in low dosage ( 300 - 450 mg/day ) . The Clinical Global Impression Improvement scale was used as the treatment outcome . A score of 1 or 2 was considered as non-response . All patients gave informed consent to participate in the study . Ratings were performed at baseline and after 1,2 and 5 weeks . Lithium plasma concentration measurements were performed after 1 and 4 weeks . After 5 weeks of augmentation , 51 % of the patients were rated as " much " or " very much " improved . Bipolar patients showed a better response than unipolar ( 64.3 % vs 45.5 % , p<0.038 ) . Most patients ( 76 % ) showed a rapid response ( up tp 7 days ) , and only 2 patients ( 4.6 % ) responded after more than 2 weeks The mean lithium plasma level was 0.33±0.09 mEq/L. No significant differences were found in treatment response with regard to sex , family history , psychotic symptomatology and suicidal ideation . No troublesome side effects were reported . Our results show that treatment augmentation with low lithium dosage may be as effective as augmentation with higher dosage , is well tolerated and does not necessitate monitoring of plasma level . Hence , an initial trial of ugmentation at low dosage lithium may be the preferred first choice in non-emergent situations . The low dosage also minimizes the risk of side effects and drug-drug interactions . Prospect i ve controlled studies to confirm our findings are needed as are larger scale comparisons with therapeutic dose lithium augmentation OBJECTIVE Poor response to long-term lithium treatment has been reported to be associated with atypical features of bipolar disorder . The purpose of this study was to investigate the influence of atypical symptoms on the effectiveness and stability of long-term lithium treatment  in a prospect i ve , multicenter cohort of bipolar patients in a naturalistic setting . METHOD Patients were initially selected according to International Classification of Diseases , 8th Revision , criteria for bipolar disorder and required long-term treatment .  Their diagnoses were reconfirmed according to DSM-IV upon its publication . They were prospect ively followed for an approximately 20-year period ending in 2004 in 5 centers participating in the International Group for the Study of Lithium-Treated Patients . Examinations included a comprehensive psychiatric evaluation , an assessment of typical and atypical features on an 8-item scale , and an evaluation of clinical course using the morbidity index . Unbalanced repeated- measures regression models with structured covariance matrices were used to assess the extent to which the morbidity index was influenced by atypical symptoms , duration of treatment , and pretreatment features . RESULTS A total of 242 patients were followed for a mean period of 10 years . In 142 patients , the number of typical features was greater than the number of atypical features , whereas in 100 patients the number of atypical features was greater than or equal to the number of typical features . The mean morbidity index remained stable over a period of 20 years in both groups of patients and was not significantly associated with the presence of atypical features , the duration of lithium treatment , the number or frequency of episodes , or latency from the onset of bipolar disorder to the start of lithium treatment . CONCLUSION Our study suggests that long-term response to lithium maintenance treatment is stable both in patients with typical and in patients with atypical features . The predominance of either typical or atypical features did not result in different responses to long-term lithium treatment in this sample of bipolar patients ABSTRACT There is no data on the variation in the suicide risk over lifetime and on the suicide-preventive effect of the long-term treatment of mood-disorder patients with antidepressants and neuroleptics .  Our research focused on 186 unipolar ( D ) , 60 bipolar II ( Dm ) , 130 nuclear bipolar I ( MD ) , and 30 preponderantly manic patients ( M/Md ) ; that were followed-up from 1963 to 2003 . By 2003 , 45 ( 11.1 % ) of the 406 patients had committed suicide . Suicide rates were highest among D patients ( St and ardized Mortality Ratio , SMR = 26.4 ) , MD ( SMR = 13.6 ) , Dm ( SMR = 10.6 ) and lowest among M/Md patients ( SMR = 4.7 ) . Prospect ively , the suicide rate decreased over the 44 years ' follow-up ; Lithium , neuroleptics and antidepressants reduced suicides significantly . Long-term treatment also reduced overall mortality , and combined treatments proved more effective than mono-therapy BACKGROUND Inferior response to lithium treatment  has been reported in bipolar disorder ( BD ) patients with mania or hypomania following episodes of major depression ( DMI ) versus preceding depression ( MDI ) , with intervening euthymic periods . However , additional characteristics of BD course-patterns require further assessment . METHODS We review ed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences . RESULTS Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals . Prevalent sequences included : major depression-hypomania ( 15.0 % ) , mania-major depression ( 14.6 % ) , major depression-mania ( 11.6 % ) , and rapid-cycling ( 9.6 % ) . Among subjects grouped by course-sequences ( based on mania , mixed-states , or hypomania and major or minor depression ) , depression-before-[hypo]mania ( DMI ) cases were more likely to be women , diagnosed BD-II , have first-episodes of depressive or anxiety disorder , spend more time ill in depression , and benefit less with long-term mood-stabilizing treatments than with the opposite pattern ( MDI ) . MDI patients were more likely to have substance-abuse and receive long-term mood-stabilizer treatments . Meta- analysis of 5 previous reports plus present findings found inferior treatment-response in DMI vs. MDI cases at a pooled risk-difference of 29 % [ CI : 18 - 40 % ] ( p<0.0001 ) . LIMITATIONS Some data were retrospective and subject to recall bias , and treatment was clinical ( non-r and omized ) . CONCLUSIONS The DMI course was strongly associated with first-episode depression or anxiety , excess depressive morbidity , and inferior treatment response , especially for depression Rationale Due to the episodic and chronic nature of bipolar disorder ( BD ) , maintenance therapy represents a critical part of treatment ; however , there is a paucity of studies comparing effectiveness of available long-term treatments . Objective The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat ( NNT ) . Methods The efficacy of drugs used for maintenance treatment of BD , as emerging from the results of r and omized controlled trials , was assessed using the size effect measure of NNT . PubMed search es were conducted on English- language articles published until May 2010 using the search terms “ bipolar disorder , ” “ mania , ” “ mixed episode , ” or “ bipolar depression , ” cross-referenced with trial characteristic search phrases and generic names of medications . The search was supplemented by manually review ing reference lists from identified publications . Results In 15 studies , aripiprazole , olanzapine , quetiapine , risperidone long-acting injection , lithium , lamotrigine , and divalproex proved effectiveness in terms of NNTs ( ≥10 % advantage over placebo ) for prevention of relapse into any mood episode . Quetiapine , lithium , risperidone long-acting injection , aripiprazole , and olanzapine are effective in manic recurrence prevention .  Lamotrigine , quetiapine , and lithium present significant NNTs for prevention of depressive relapses . Conclusions All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode ; however , different efficacy profiles were found for prevention of manic and /or depressive relapses . The comparison of NNT values of the available agents may represent a useful tool in clinical setting s , in order to facilitate implementation of long-term pharmacological interventions in patients with BD Recent findings have indicated that lithium treatment markedly reduces  suicide risk in major affective disorders . To compare the effect of lithium with carbamazepine and amitriptyline , suicidal behavior was analyzed during the r and omized prospect i ve long-term MAP study ( N = 378 ; duration 2.5 years ) . Of the nine suicides and five attempted suicides , none took place during lithium treatment . The findings support the view that lithium has a specific antisuicidal effect over and above its prophylactic benefit In a r and omized clinical trial with an observation period of 2.5 years , the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients ( DSM-IV ) . In order to investigate the efficacy of the two drugs in clearly defined sub sample s , a series of subgroup analyses was carried out . First , patients with a bipolar I disorder ( n = 114 ) were analyzed separately . In these patients , lithium was superior to carbamazepine . In contrast , carbamazepine was at least equally as efficacious as lithium in the sub sample of patients with bipolar II disorder or bipolar disorder not otherwise specified ( n = 57 ) . In a second analysis on differential efficacy , the whole sample was subdivided into a classical subgroup ( bipolar I patients without mood-incongruent delusions and without comorbidity ; n = 67 ) and a nonclassical subgroup including all other patients ( n = 104 ) . Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis ( 26 vs. 62 % , p = 0.012 ) . For the nonclassical group , a tendency in favor of carbamazepine was found . In a third step , we analyzed the impact of episode sequence on differential efficacy . In a global view , the episode sequence prior to the index episode was not correlated to differential efficacy . Our results might , however , indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium . Besides differential efficacy , suicidal behavior and patients ’ satisfaction with treatment were investigated . Regarding suicidal behavior , a trend in favor of lithium was found . The data on patients ’ satisfaction were significantly in favor of carbamazepine . In conclusion , lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide . The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients . Hence , treatment alternatives to lithium are desirable for the majority of bipolar patients Design s used with success in therapeutic experiments are not necessarily suited to prophylactic trials , which offer special problems and require that new experimental procedures and statistical methods are employed . Controlled prophylactic trials may be carried out in two different ways : ( i ) Concurrent comparison of the course of the disease in an experimental patient group and a control group , and ( ii ) studies on a single group of  patients during successive control periods and drug periods . Each procedure offers advantages and disadvantages ; ethical problems are of particular importance . Special attention should be given to the definition of patient sample s and to the criteria chosen for recording a relapse . Experiments must be design ed with consideration of the role played by non-pharmacological factors : spontaneous variation of the disease course during treatment , the psychological effects of the treatment , and observer bias OBJECTIVE We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood . METHOD 529 adult out patients with a mean age of 42 years , who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria , were rated prospect ively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years . RESULTS Fifty percent of patients had illness onset in childhood ( < 13 years of age 
    Output:
    
agent
Conclusions Lithium continues as the st and ard and most extensively evaluated treatment for bipolar disorder , especially for long-term prophylaxis
***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: Lithium augmentation is one of the best studied strategies for resistant depression . The lithium dosage usually given is around 900 mg/day and plasma level is maintained in the range of 0.5 - 0.8 mEq/L. However , the administration of lithium in this dosage necessitates monitoring of plasma concentration and increases the risk of toxicity and side effects . Since it has been shown that low lithium levels increase serotonin turnover and enhance serotonin neurotransmission , we thought it of interest to assess the efficacy of low dosage lithium augmentation for patients with resistant depression . Fifty one patients suffering from severe unipolar or bipolar depression who had failed to respond to treatment with venlafaxine 300 - 375 mg/day were included in the study and treated as out patients . Patients had previously been exposed to unsuccessful treatment with various antidepressants , mostly SSRIs . After a washout period for previously administered antidepressants of one week , the dosage of venlafaxine was rapidly titrated to 300 or 375 mg/day , corresponding to about 5 mg/kg . The dose remained stable during the next six weeks . Additional antipsychotic medication was allowed to treat psychotic symptoms . Forty seven severely depressed patients who failed to respond to 300 - 375 mg/day venlafaxine  were , in addition , given lithium carbonate in low dosage ( 300 - 450 mg/day ) . The Clinical Global Impression Improvement scale was used as the treatment outcome . A score of 1 or 2 was considered as non-response . All patients gave informed consent to participate in the study . Ratings were performed at baseline and after 1,2 and 5 weeks . Lithium plasma concentration measurements were performed after 1 and 4 weeks . After 5 weeks of augmentation , 51 % of the patients were rated as " much " or " very much " improved . Bipolar patients showed a better response than unipolar ( 64.3 % vs 45.5 % , p<0.038 ) . Most patients ( 76 % ) showed a rapid response ( up tp 7 days ) , and only 2 patients ( 4.6 % ) responded after more than 2 weeks The mean lithium plasma level was 0.33±0.09 mEq/L. No significant differences were found in treatment response with regard to sex , family history , psychotic symptomatology and suicidal ideation . No troublesome side effects were reported . Our results show that treatment augmentation with low lithium dosage may be as effective as augmentation with higher dosage , is well tolerated and does not necessitate monitoring of plasma level . Hence , an initial trial of ugmentation at low dosage lithium may be the preferred first choice in non-emergent situations . The low dosage also minimizes the risk of side effects and drug-drug interactions . Prospect i ve controlled studies to confirm our findings are needed as are larger scale comparisons with therapeutic dose lithium augmentation OBJECTIVE Poor response to long-term lithium treatment has been reported to be associated with atypical features of bipolar disorder . The purpose of this study was to investigate the influence of atypical symptoms on the effectiveness and stability of long-term lithium treatment  in a prospect i ve , multicenter cohort of bipolar patients in a naturalistic setting . METHOD Patients were initially selected according to International Classification of Diseases , 8th Revision , criteria for bipolar disorder and required long-term treatment .  Their diagnoses were reconfirmed according to DSM-IV upon its publication . They were prospect ively followed for an approximately 20-year period ending in 2004 in 5 centers participating in the International Group for the Study of Lithium-Treated Patients . Examinations included a comprehensive psychiatric evaluation , an assessment of typical and atypical features on an 8-item scale , and an evaluation of clinical course using the morbidity index . Unbalanced repeated- measures regression models with structured covariance matrices were used to assess the extent to which the morbidity index was influenced by atypical symptoms , duration of treatment , and pretreatment features . RESULTS A total of 242 patients were followed for a mean period of 10 years . In 142 patients , the number of typical features was greater than the number of atypical features , whereas in 100 patients the number of atypical features was greater than or equal to the number of typical features . The mean morbidity index remained stable over a period of 20 years in both groups of patients and was not significantly associated with the presence of atypical features , the duration of lithium treatment , the number or frequency of episodes , or latency from the onset of bipolar disorder to the start of lithium treatment . CONCLUSION Our study suggests that long-term response to lithium maintenance treatment is stable both in patients with typical and in patients with atypical features . The predominance of either typical or atypical features did not result in different responses to long-term lithium treatment in this sample of bipolar patients ABSTRACT There is no data on the variation in the suicide risk over lifetime and on the suicide-preventive effect of the long-term treatment of mood-disorder patients with antidepressants and neuroleptics .  Our research focused on 186 unipolar ( D ) , 60 bipolar II ( Dm ) , 130 nuclear bipolar I ( MD ) , and 30 preponderantly manic patients ( M/Md ) ; that were followed-up from 1963 to 2003 . By 2003 , 45 ( 11.1 % ) of the 406 patients had committed suicide . Suicide rates were highest among D patients ( St and ardized Mortality Ratio , SMR = 26.4 ) , MD ( SMR = 13.6 ) , Dm ( SMR = 10.6 ) and lowest among M/Md patients ( SMR = 4.7 ) . Prospect ively , the suicide rate decreased over the 44 years ' follow-up ; Lithium , neuroleptics and antidepressants reduced suicides significantly . Long-term treatment also reduced overall mortality , and combined treatments proved more effective than mono-therapy BACKGROUND Inferior response to lithium treatment  has been reported in bipolar disorder ( BD ) patients with mania or hypomania following episodes of major depression ( DMI ) versus preceding depression ( MDI ) , with intervening euthymic periods . However , additional characteristics of BD course-patterns require further assessment . METHODS We review ed computerized clinical records and life-charts of 855 DSM-IV-TR BD-I or -II patients assessed and followed at mood-disorder centers in Cagliari or Rome to characterize their predominant course-sequences . RESULTS Morbidity over an average of 9.5 cycles in 18 years was characterized for sequencing of illness-episodes and euthymic intervals . Prevalent sequences included : major depression-hypomania ( 15.0 % ) , mania-major depression ( 14.6 % ) , major depression-mania ( 11.6 % ) , and rapid-cycling ( 9.6 % ) . Among subjects grouped by course-sequences ( based on mania , mixed-states , or hypomania and major or minor depression ) , depression-before-[hypo]mania ( DMI ) cases were more likely to be women , diagnosed BD-II , have first-episodes of depressive or anxiety disorder , spend more time ill in depression , and benefit less with long-term mood-stabilizing treatments than with the opposite pattern ( MDI ) . MDI patients were more likely to have substance-abuse and receive long-term mood-stabilizer treatments . Meta- analysis of 5 previous reports plus present findings found inferior treatment-response in DMI vs. MDI cases at a pooled risk-difference of 29 % [ CI : 18 - 40 % ] ( p<0.0001 ) . LIMITATIONS Some data were retrospective and subject to recall bias , and treatment was clinical ( non-r and omized ) . CONCLUSIONS The DMI course was strongly associated with first-episode depression or anxiety , excess depressive morbidity , and inferior treatment response , especially for depression Rationale Due to the episodic and chronic nature of bipolar disorder ( BD ) , maintenance therapy represents a critical part of treatment ; however , there is a paucity of studies comparing effectiveness of available long-term treatments . Objective The aim of this study is to determine and compare the efficacy of pharmacological treatments for maintenance treatment of BD by means of the number needed to treat ( NNT ) . Methods The efficacy of drugs used for maintenance treatment of BD , as emerging from the results of r and omized controlled trials , was assessed using the size effect measure of NNT . PubMed search es were conducted on English- language articles published until May 2010 using the search terms “ bipolar disorder , ” “ mania , ” “ mixed episode , ” or “ bipolar depression , ” cross-referenced with trial characteristic search phrases and generic names of medications . The search was supplemented by manually review ing reference lists from identified publications . Results In 15 studies , aripiprazole , olanzapine , quetiapine , risperidone long-acting injection , lithium , lamotrigine , and divalproex proved effectiveness in terms of NNTs ( ≥10 % advantage over placebo ) for prevention of relapse into any mood episode . Quetiapine , lithium , risperidone long-acting injection , aripiprazole , and olanzapine are effective in manic recurrence prevention .  Lamotrigine , quetiapine , and lithium present significant NNTs for prevention of depressive relapses . Conclusions All of the pharmacological agents assessed were effective in the prevention of any kind of mood episode ; however , different efficacy profiles were found for prevention of manic and /or depressive relapses . The comparison of NNT values of the available agents may represent a useful tool in clinical setting s , in order to facilitate implementation of long-term pharmacological interventions in patients with BD Recent findings have indicated that lithium treatment markedly reduces  suicide risk in major affective disorders . To compare the effect of lithium with carbamazepine and amitriptyline , suicidal behavior was analyzed during the r and omized prospect i ve long-term MAP study ( N = 378 ; duration 2.5 years ) . Of the nine suicides and five attempted suicides , none took place during lithium treatment . The findings support the view that lithium has a specific antisuicidal effect over and above its prophylactic benefit In a r and omized clinical trial with an observation period of 2.5 years , the differential efficacy of lithium versus carbamazepine was compared in 171 bipolar patients ( DSM-IV ) . In order to investigate the efficacy of the two drugs in clearly defined sub sample s , a series of subgroup analyses was carried out . First , patients with a bipolar I disorder ( n = 114 ) were analyzed separately . In these patients , lithium was superior to carbamazepine . In contrast , carbamazepine was at least equally as efficacious as lithium in the sub sample of patients with bipolar II disorder or bipolar disorder not otherwise specified ( n = 57 ) . In a second analysis on differential efficacy , the whole sample was subdivided into a classical subgroup ( bipolar I patients without mood-incongruent delusions and without comorbidity ; n = 67 ) and a nonclassical subgroup including all other patients ( n = 104 ) . Classical bipolar patients had a significantly lower hospitalization rate under lithium than under carbamazepine prophylaxis ( 26 vs. 62 % , p = 0.012 ) . For the nonclassical group , a tendency in favor of carbamazepine was found . In a third step , we analyzed the impact of episode sequence on differential efficacy . In a global view , the episode sequence prior to the index episode was not correlated to differential efficacy . Our results might , however , indicate that patients with an episode sequence of mania-depression-free interval responded better to lithium . Besides differential efficacy , suicidal behavior and patients ’ satisfaction with treatment were investigated . Regarding suicidal behavior , a trend in favor of lithium was found . The data on patients ’ satisfaction were significantly in favor of carbamazepine . In conclusion , lithium appears to be superior to carbamazepine in classical bipolar cases and might have additional impact on proneness to suicide . The distinctly larger group of patients with nonclassical features might profit more from carbamazepine which seems to be well accepted by the patients . Hence , treatment alternatives to lithium are desirable for the majority of bipolar patients Design s used with success in therapeutic experiments are not necessarily suited to prophylactic trials , which offer special problems and require that new experimental procedures and statistical methods are employed . Controlled prophylactic trials may be carried out in two different ways : ( i ) Concurrent comparison of the course of the disease in an experimental patient group and a control group , and ( ii ) studies on a single group of  patients during successive control periods and drug periods . Each procedure offers advantages and disadvantages ; ethical problems are of particular importance . Special attention should be given to the definition of patient sample s and to the criteria chosen for recording a relapse . Experiments must be design ed with consideration of the role played by non-pharmacological factors : spontaneous variation of the disease course during treatment , the psychological effects of the treatment , and observer bias OBJECTIVE We examined the influence of age at onset of illness and the delay in time to first treatment on morbidity in adulthood . METHOD 529 adult out patients with a mean age of 42 years , who entered our research network from 1996 through 2001 and who were diagnosed with bipolar disorder according to DSM-IV criteria , were rated prospect ively on a daily basis with the National Institute of Mental Health-Life Chart Method during naturalistic treatment for up to 4 years . RESULTS Fifty percent of patients had illness onset in childhood ( < 13 years of age 
    Output:
    