title: Low dosage lithium augmentation in venlafaxine resistant depression: an open-label study. Long-term effectiveness of lithium in bipolar disorder: a multicenter investigation of patients with typical and atypical features. Suicide in 406 Mood-Disorder Patients With and Without Long-Term Medication: A 40 to 44 Years' Follow-Up Course sequences in bipolar disorder: depressions preceding or following manias or hypomanias. Number needed to treat analyses of drugs used for maintenance treatment of bipolar disorder Effect of prophylactic treatment on suicide risk in patients with major affective disorders. Data from a randomized prospective trial. Differential Efficacy of Lithium and Carbamazepine in the Prophylaxis of Bipolar Disorder: Results of the MAP Study Methodological problems of prophylactic trials in recurrent affective disorders. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. Outcome after rapid vs gradual discontinuation of lithium treatment in bipolar disorders. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders.
abstract: 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 ) or adolescence ( 13 - 18 years of age ) . In year 1 of follow-up , these patients , compared to those with adult onset , showed significantly ( P<.05 ) greater severity of depression and mania , greater number of episodes , more days depressed , more days of ultradian cycling , and fewer days euthymic . After 4 years , the mean severity and duration of depression remained greater and the number of days euthymic fewer in those with childhood compared to adult onset ( P<.05 ) . The delays to first treatment correlated inversely with age at onset of illness . Independently , delay to first treatment was associated with more time depressed , greater severity of depression , greater number of episodes , more days of ultradian cycling , and fewer days euthymic ( all P<.05 ) . CONCLUSIONS These data converge with other evidence that onset of bipolar disorder in childhood is common and often associated with extraordinarily long delays to first pharmacologic treatment . Both childhood onset and treatment delay were associated with a persistently more adverse course of illness rated prospect ively in adults . These data should help foster efforts to ensure earlier and more effective treatment of bipolar illness in children and adolescents . It is hoped that appropriate early intervention would result in a more benign illness and a better prognosis in adulthood OBJECTIVE Withdrawal of bipolar mood disorder ( BP-I ) patients from prolonged , stable lithium maintenance has a high risk of early recurrence , particularly of mania . We thus compared risks of stopping lithium rapidly vs gradually . DESIGN Out patients undergoing clinical ly determined discontinuation of lithium treatment at different rates were followed up prospect ively to 5 years . Risks and timing of new episodes were analyzed . PATIENTS Subjects ( N = 64 ) with a DSM-III-R BP disorder , previously stable on lithium monotherapy for 18 to 120 months ( mean , 3.6 years ) were followed up clinical ly after discontinuing lithium ( elected in prolonged wellbeing in 67 % ) . None was unavailable for follow-up , and subtyping ( BP-I or BP-II ) remained stable . RESULTS Within 5 years , 75 % had a recurrent episode ; BP-I patients were 1.5-times less likely than BP-II to remain in remission . Polarity of first-recurrent and onset episodes was 80.8 % concordant . Overall risk of a new episode of mania was significantly greater after rapid ( < 2 ) than gradual ( 2 to 4 weeks discontinuation ( 5-year hazard ratio = 2.8 ) ; the difference in risk of depression was even greater hazard ratio = 5.4 ) . Recurrence rate was more elevated within months of rapid discontinuation ( 12-month hazard ratio = 5.4 ) . Recurrence rate was more elevated within months of rapid discontinuation ( 12-month hazard ratio = 4.3 ) than at later times ( 2 to 5 years ) , when courses of " survival " over time were nearly parallel in both discontinuation groups . CONCLUSIONS Risk of early recurrence of BP disorder following discontinuation of lithium maintenance is elevated , but may be both predictable ( timing and polarity ) and modifiable by gradual discontinuation Abstract Fifty manic-depressive patients and thirty-four patients with recurrent endogenous depression who had been on open lithium treatment for at least a year took part in double-blind discontinuance studies to compare lithium carbonate and placebo . Within each diagnostic group matched pairs were allocated at r and om to lithium carbonate or placebo .  Relapses occurring first in the lithium partners constituted placebo preferences and those occurring first in the placebo parners lithium preferences . Relapses were recorded when requiring hospital admission or supervision with additional therapy at home . Serum-lithium levels were monitored . The trials terminated in significant preference for lithium both in manic-depressive and in recurrent-depressive disorder ; this happened when nine patients in each group had relapsed on placebo and none on lithium . During the whole trial , which lasted five months , twenty-one placebo patients relapsed and none of the lithium patients . Before the trials , patients had been on lithium for up to 7 years ; even after this long period there was still risk of relapse on withdrawal of the drug
target: Conclusions Lithium continues as the st and ard and most extensively evaluated treatment for bipolar disorder , especially for long-term prophylaxis
background: Background Lithium has been used clinical ly for 70 years , mainly to treat bipolar disorder .
  Competing treatments and exaggerated impressions about complexity and risks of lithium treatment have led to its declining use in some countries , encouraging this up date about its safe clinical use .