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: There is a pressing need for additional treatment options for refractory mood disorders . This controlled comparative study evaluated the efficacy of lamotrigine ( LTG ) and gabapentin ( GBP ) monotherapy versus placebo ( PLC ) .  Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind , r and omized , crossover series of three 6-week monotherapy evaluations including LTG , GBP , and PLC . There was a st and ardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose ( LTG 500 mg or GBP 4,800 mg ) . The primary outcome measure was the Clinical Global Impressions Scale ( CGI ) for Bipolar Illness as supplemented by other st and ard rating instruments . The mean doses at week 6 were 274 + /- 128 mg for LTG and 3,987 + /- 856 mg for GBP . Response rates ( CGI ratings of much or very much improved ) were the following : LTG , 52 % ( 16/31 ) ; GBP , 26 % ( 8/31 ) ; and PLC , 23 % ( 7/31 ) ( Cochran 's Q = 6.952 , df = 2 , N = 31 , p = 0.031 ) . Post hoc Q differences ( df = 1 , N = 31 ) were the following : LTG versus GBP ( Qdiff = 5.33 , p = 0.011 ) ; LTG versus PLC ( Qdiff = 4.76 , p = 0.022 ) ; and GBP versus PLC ( Qdiff = 0.08 , p = 0.70 ) . With respect to anticonvulsant dose and gender , there was no difference between the responders and the nonresponders . The agents were generally well tolerated . This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients . Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study OBJECTIVE To determine the efficacy of divalproex ( extended release ) in the treatment of acute nonrefractory bipolar depression . METHOD In a stratified , double-blind , r and omized , placebo-controlled trial , 18 acutely depressed bipolar out patients ( DSM-IV criteria ) received either divalproex monotherapy ( target dose level , 70 - 90 ng/dL ) ( N = 9 ) or placebo ( N = 9 ) for 6 weeks . Patients were recruited between January 2004 and May 2005 . Clinical assessment on the Montgomery-Asberg Depression Rating Scale ( MADRS ) determined primary efficacy . RESULTS The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo ( group x time interaction , p = .0078 ) . Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo ( p = .003 , linear growth curve model ) . St and ardized effect size was large ( Cohen d = 0.81 ) . MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms . There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group ( r = 0.29 , df = 51 , p = .03 ) , but not in the placebo group ( r = -0.15 , df = 35 , p = .36 ) . CONCLUSIONS Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression , which is consistent with previous small r and omized studies . Some evidence of benefit in the depressive mixed state was observed . Confirmation or refutation with larger r and omized clinical trials is warranted . CLINICAL TRIAL REGISTRATION Clinical Trials.gov identifier NCT00226343 BACKGROUND To our knowledge , this is the first prospect i ve natural history study of weekly symptomatic status of patients with bipolar I disorder ( BP-I ) during long-term follow-up . METHODS Analyses are based on ongoing prospect i ve follow-up of 146 patients with Research Diagnostic Criteria BP-I , who entered the National Institute of Mental Health ( Bethesda , Md ) Collaborative Depression Study from 1978 through 1981 .  Weekly affective symptom status ratings were analyzed by polarity and severity , ranging from asymptomatic , to subthreshold levels , to full-blown major depression and mania . Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined . Finally , 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. RESULTS Patients with BP-I were symptomatically ill 47.3 % of weeks throughout a mean of 12.8 years of follow-up . Depressive symptoms ( 31.9 % of total follow-up weeks ) predominated over manic/hypomanic symptoms ( 8.9 % of weeks ) or cycling/mixed symptoms ( 5.9 % of weeks ) . Subsyndromal , minor depressive , and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms ( 29.9 % vs 11.2 % of weeks , respectively ) . Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year . Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up , as did comorbid drug-use disorder . CONCLUSIONS The longitudinal weekly symptomatic course of BP-I is chronic . Overall , the symptomatic structure is primarily depressive rather than manic , and subsyndromal and minor affective symptoms predominate . Symptom severity levels fluctuate , often within the same patient over time . Bipolar I disorder is expressed as a dimensional illness featuring the full range ( spectrum ) of affective symptom severity and polarity BACKGROUND Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials . This double-blind , placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder . METHODS After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued , patients were r and omized to lamotrigine ( 100 - 400 mg daily ) , lithium ( 0.8 - 1.1 mEq/L ) , or placebo as double-blind maintenance treatment for as long as 18 months . RESULTS Of 349 patients who met screening criteria and entered the open-label phase , 175 met stabilization criteria and were r and omized to double-blind maintenance treatment  ( lamotrigine , 59 patients ; lithium , 46 patients ; and placebo , 70 patients ) . Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode  ( lamotrigine vs placebo , P = .02 ; lithium vs placebo , P = .006 ) . Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02 ) . Lithium was superior to placebo at prolonging the time to a manic , hypomanic , or mixed episode ( P = .006 ) . The most common adverse event reported for lamotrigine was headache . CONCLUSIONS Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode . The results indicate that lamotrigine is an effective , well-tolerated maintenance treatment for bipolar disorder , particularly for prophylaxis of depression OBJECTIVE Clinicians have few evidence -based options for the management of treatment-resistant bipolar depression .  This study represents the first r and omized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine , inositol , and risperidone . METHOD Participants ( N=66 ) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) . All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant . Patients were r and omly assigned to open-label adjunctive treatment with lamotrigine , inositol , or risperidone for up to 16 weeks . The primary outcome measure was the rate of recovery , defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks . RESULTS No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure . However , the recovery rate with lamotrigine was 23.8 % , whereas the recovery rates with inositol and risperidone were 17.4 % and 4.6 % , respectively . Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone . CONCLUSIONS No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine , inositol , or risperidone . Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression BACKGROUND Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life . AIMS To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes . METHOD In a double-blind r and omised maintenance trial , patients received either olanzapine or lithium monotherapy for 1 year . Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms . The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse . RESULTS Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse ( relative risk 4.67 , P<0.001 ) . Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms ( RR=2.51 , P<0.001 and RR=2.35 , P=0.03 respectively ) . CONCLUSIONS These findings help to identify patients at increased risk of affective relapse  and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent The authors evaluated carbamazepine ( Tegretol ) , a drug of choice for treatment of temporal lobe epilepsy , in a double-blind placebo-controlled trial in patients with manic-depressive illness . Seven of 9 manic patients had a partial to marked response ; several also showed relapses when placebo was substituted and improvement when carbamazepine was reinstituted . Five of 13 depressed patients showed significant improvement in depression ratings ; 3 additional patients experienced partial relapse when placebo was substituted . Carbamazepine might also have prophylactic as well as acute efficacy in patients with both phases of manic-depressive illness , including some patients who do not respond to lithium . Therapeutic effects were achieved with 600 - 1600 mg/day at blood levels of 8 - 12 microgram/ml with relatively few side effects .  Carbamazepine may prove to be a useful additional treatment for affective illness OBJECTIVE Determine the efficacy and tolerability of olanzapine/fluoxetine combination ( OFC ) for treatment of acute bipolar I depression compared with lamotrigine . METHOD The 7-week , acute phase of a r and omized , double-blind study compared OFC ( 6/25 , 6/50 , 12/25 , or 12/50 mg/day ; N = 205 ) with lamotrigine ( [ LMG ] titrated to 200 mg/day ; N = 205 ) in patients with DSM-IV-diagnosed bipolar I disorder , depressed . The study was conducted from November 2003 to August 2004 . RESULTS Completion rates were similar between treatments ( OFC , 66.8 % vs. LMG , 65.4 % ; p = .835 ) . OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale ( primary outcome ) ( p = .002 , effect size = 0.26 ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) ( p = .002 , effect size = 0.24 ) , and Young Mania Rating Scale total scores ( 
    Output:
    
agent
Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect .
Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant .
All anticonvulsants were generally well tolerated .
No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine , licarbazepine , zonisamide , retigabine , pregabalin , tiagabine , felbamate and vigabatrine in the acute treatment of bipolar depression .
To sum up , taking into consideration the efficacy and tolerability profiles of anticonvulsants , current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression .
***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: There is a pressing need for additional treatment options for refractory mood disorders . This controlled comparative study evaluated the efficacy of lamotrigine ( LTG ) and gabapentin ( GBP ) monotherapy versus placebo ( PLC ) .  Thirty-one patients with refractory bipolar and unipolar mood disorders participated in a double-blind , r and omized , crossover series of three 6-week monotherapy evaluations including LTG , GBP , and PLC . There was a st and ardized blinded titration to assess clinical efficacy or to determine the maximum tolerated daily dose ( LTG 500 mg or GBP 4,800 mg ) . The primary outcome measure was the Clinical Global Impressions Scale ( CGI ) for Bipolar Illness as supplemented by other st and ard rating instruments . The mean doses at week 6 were 274 + /- 128 mg for LTG and 3,987 + /- 856 mg for GBP . Response rates ( CGI ratings of much or very much improved ) were the following : LTG , 52 % ( 16/31 ) ; GBP , 26 % ( 8/31 ) ; and PLC , 23 % ( 7/31 ) ( Cochran 's Q = 6.952 , df = 2 , N = 31 , p = 0.031 ) . Post hoc Q differences ( df = 1 , N = 31 ) were the following : LTG versus GBP ( Qdiff = 5.33 , p = 0.011 ) ; LTG versus PLC ( Qdiff = 4.76 , p = 0.022 ) ; and GBP versus PLC ( Qdiff = 0.08 , p = 0.70 ) . With respect to anticonvulsant dose and gender , there was no difference between the responders and the nonresponders . The agents were generally well tolerated . This controlled investigation preliminarily suggests the efficacy of LTG in treatment-refractory affectively ill patients . Further definition of responsive subtypes and the role of these medications in the treatment of mood disorders requires additional study OBJECTIVE To determine the efficacy of divalproex ( extended release ) in the treatment of acute nonrefractory bipolar depression . METHOD In a stratified , double-blind , r and omized , placebo-controlled trial , 18 acutely depressed bipolar out patients ( DSM-IV criteria ) received either divalproex monotherapy ( target dose level , 70 - 90 ng/dL ) ( N = 9 ) or placebo ( N = 9 ) for 6 weeks . Patients were recruited between January 2004 and May 2005 . Clinical assessment on the Montgomery-Asberg Depression Rating Scale ( MADRS ) determined primary efficacy . RESULTS The divalproex treatment group showed significantly greater reduction in MADRS scores compared to placebo ( group x time interaction , p = .0078 ) . Absolute effect size of estimated MADRS total score reduction over time was 13.6 points with divalproex versus 1.4 points with placebo ( p = .003 , linear growth curve model ) . St and ardized effect size was large ( Cohen d = 0.81 ) . MADRS item analyses demonstrated improvement in core mood symptoms more than in anxiety or insomnia symptoms . There was also a modest but significant association between MADRS and Mania Rating Scale scores in the divalproex group ( r = 0.29 , df = 51 , p = .03 ) , but not in the placebo group ( r = -0.15 , df = 35 , p = .36 ) . CONCLUSIONS Divalproex appeared to be an effective treatment for acute nonrefractory bipolar depression , which is consistent with previous small r and omized studies . Some evidence of benefit in the depressive mixed state was observed . Confirmation or refutation with larger r and omized clinical trials is warranted . CLINICAL TRIAL REGISTRATION Clinical Trials.gov identifier NCT00226343 BACKGROUND To our knowledge , this is the first prospect i ve natural history study of weekly symptomatic status of patients with bipolar I disorder ( BP-I ) during long-term follow-up . METHODS Analyses are based on ongoing prospect i ve follow-up of 146 patients with Research Diagnostic Criteria BP-I , who entered the National Institute of Mental Health ( Bethesda , Md ) Collaborative Depression Study from 1978 through 1981 .  Weekly affective symptom status ratings were analyzed by polarity and severity , ranging from asymptomatic , to subthreshold levels , to full-blown major depression and mania . Percentages of follow-up weeks at each level as well as number of shifts in symptom status and polarity during the entire follow-up period were examined . Finally , 2 new measures of chronicity were evaluated in relation to previously identified predictors of chronicity for BP-I. RESULTS Patients with BP-I were symptomatically ill 47.3 % of weeks throughout a mean of 12.8 years of follow-up . Depressive symptoms ( 31.9 % of total follow-up weeks ) predominated over manic/hypomanic symptoms ( 8.9 % of weeks ) or cycling/mixed symptoms ( 5.9 % of weeks ) . Subsyndromal , minor depressive , and hypomanic symptoms combined were nearly 3 times more frequent than syndromal-level major depressive and manic symptoms ( 29.9 % vs 11.2 % of weeks , respectively ) . Patients with BP-I changed symptom status an average of 6 times per year and polarity more than 3 times per year . Longer intake episodes and those with depression-only or cycling polarity predicted greater chronicity during long-term follow-up , as did comorbid drug-use disorder . CONCLUSIONS The longitudinal weekly symptomatic course of BP-I is chronic . Overall , the symptomatic structure is primarily depressive rather than manic , and subsyndromal and minor affective symptoms predominate . Symptom severity levels fluctuate , often within the same patient over time . Bipolar I disorder is expressed as a dimensional illness featuring the full range ( spectrum ) of affective symptom severity and polarity BACKGROUND Lamotrigine has been shown to be an effective treatment for bipolar depression and rapid cycling in placebo-controlled clinical trials . This double-blind , placebo-controlled study was conducted to assess the efficacy and tolerability of lamotrigine and lithium compared with placebo for the prevention of relapse or recurrence of mood episodes in recently manic or hypomanic patients with bipolar I disorder . METHODS After an 8- to 16-week open-label phase during which treatment with lamotrigine was initiated and other psychotropic drug regimens were discontinued , patients were r and omized to lamotrigine ( 100 - 400 mg daily ) , lithium ( 0.8 - 1.1 mEq/L ) , or placebo as double-blind maintenance treatment for as long as 18 months . RESULTS Of 349 patients who met screening criteria and entered the open-label phase , 175 met stabilization criteria and were r and omized to double-blind maintenance treatment  ( lamotrigine , 59 patients ; lithium , 46 patients ; and placebo , 70 patients ) . Both lamotrigine and lithium were superior to placebo at prolonging the time to intervention for any mood episode  ( lamotrigine vs placebo , P = .02 ; lithium vs placebo , P = .006 ) . Lamotrigine was superior to placebo at prolonging the time to a depressive episode ( P = .02 ) . Lithium was superior to placebo at prolonging the time to a manic , hypomanic , or mixed episode ( P = .006 ) . The most common adverse event reported for lamotrigine was headache . CONCLUSIONS Both lamotrigine and lithium were superior to placebo for the prevention of relapse or recurrence of mood episodes in patients with bipolar I disorder who had recently experienced a manic or hypomanic episode . The results indicate that lamotrigine is an effective , well-tolerated maintenance treatment for bipolar disorder , particularly for prophylaxis of depression OBJECTIVE Clinicians have few evidence -based options for the management of treatment-resistant bipolar depression .  This study represents the first r and omized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine , inositol , and risperidone . METHOD Participants ( N=66 ) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder ( STEP-BD ) . All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant . Patients were r and omly assigned to open-label adjunctive treatment with lamotrigine , inositol , or risperidone for up to 16 weeks . The primary outcome measure was the rate of recovery , defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks . RESULTS No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure . However , the recovery rate with lamotrigine was 23.8 % , whereas the recovery rates with inositol and risperidone were 17.4 % and 4.6 % , respectively . Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone . CONCLUSIONS No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine , inositol , or risperidone . Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression BACKGROUND Sub-syndromal symptoms in bipolar disorder impair functioning and diminish quality of life . AIMS To examine factors associated with time spent with sub-syndromal symptoms and to characterise how these symptoms influence outcomes . METHOD In a double-blind r and omised maintenance trial , patients received either olanzapine or lithium monotherapy for 1 year . Stepwise logistic regression models were used to identify factors that were significant predictors of percentage time spent with sub-syndromal symptoms . The presence of sub-syndromal symptoms during the first 8 weeks was examined as a predictor of subsequent relapse . RESULTS Presence of sub-syndromal depressive symptoms during the first 8 weeks significantly increased the likelihood of depressive relapse ( relative risk 4.67 , P<0.001 ) . Patients with psychotic features and those with a greater number of previous depressive episodes were more likely to experience sub-syndromal depressive symptoms ( RR=2.51 , P<0.001 and RR=2.35 , P=0.03 respectively ) . CONCLUSIONS These findings help to identify patients at increased risk of affective relapse  and suggest that appropriate therapeutic interventions should be considered even when syndromal-level symptoms are absent The authors evaluated carbamazepine ( Tegretol ) , a drug of choice for treatment of temporal lobe epilepsy , in a double-blind placebo-controlled trial in patients with manic-depressive illness . Seven of 9 manic patients had a partial to marked response ; several also showed relapses when placebo was substituted and improvement when carbamazepine was reinstituted . Five of 13 depressed patients showed significant improvement in depression ratings ; 3 additional patients experienced partial relapse when placebo was substituted . Carbamazepine might also have prophylactic as well as acute efficacy in patients with both phases of manic-depressive illness , including some patients who do not respond to lithium . Therapeutic effects were achieved with 600 - 1600 mg/day at blood levels of 8 - 12 microgram/ml with relatively few side effects .  Carbamazepine may prove to be a useful additional treatment for affective illness OBJECTIVE Determine the efficacy and tolerability of olanzapine/fluoxetine combination ( OFC ) for treatment of acute bipolar I depression compared with lamotrigine . METHOD The 7-week , acute phase of a r and omized , double-blind study compared OFC ( 6/25 , 6/50 , 12/25 , or 12/50 mg/day ; N = 205 ) with lamotrigine ( [ LMG ] titrated to 200 mg/day ; N = 205 ) in patients with DSM-IV-diagnosed bipolar I disorder , depressed . The study was conducted from November 2003 to August 2004 . RESULTS Completion rates were similar between treatments ( OFC , 66.8 % vs. LMG , 65.4 % ; p = .835 ) . OFC-treated patients had significantly greater improvement than lamotrigine-treated patients in change from baseline across the 7-week treatment period on the Clinical Global Impressions-Severity of Illness scale ( primary outcome ) ( p = .002 , effect size = 0.26 ) , Montgomery-Asberg Depression Rating Scale ( MADRS ) ( p = .002 , effect size = 0.24 ) , and Young Mania Rating Scale total scores ( 
    Output:
    