Formulation of a gabapentin drug degradation model that combines manufacturing and storage stress variables T. Radaduen, S. Stamatis, H. Q. Nguyen, Z. Zong, L. E. Kirsch National Institute for Pharmaceutical Technology and Education and The University of Iowa The objective of these studies was to formulate a drug degradation model that incorporated environmental storage and manufacturing stress f
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Strategies for preventing the recurrence of bipolar disorderStrategies for Preventing the Recurrence of Bipolar Disorder
S. Nassir Ghaemi, M.D.; Tamara B. Pardo, A.B.; and Douglas J. Hsu, B.S.
In interpreting the maintenance literature for bipolar disorder, attention needs to be paid to impor- tant methodological issues. In this article, we initially examine the methodological topics that need tobe considered, and we then examine the content of the evidence regarding maintenance treatments.
Agents used in the long-term treatment of bipolar disorder possess varying degrees of supportive evi-dence. By consensus, the number of randomized studies and years of clinical experience with lithiummark it as the evidentially strongest long-term agent for bipolar disorder. Recent studies also demon-strate likely long-term benefit with lamotrigine, and possibly olanzapine. Although we possess fewerrandomized data, some such evidence exists and, along with clinical experience, supports the likelylong-term utility of valproate in the treatment of bipolar disorder as well. Some psychotherapies alsomay possess adjunctive maintenance efficacy.
(J Clin Psychiatry 2004;65[suppl 10]:16–23) Another methodological issue to highlight is the differ- ence between continuation and maintenance treatments.
Several methodological guidelines (Table 1)1 are im- The acute phase of recovery is commonly defined as the 2 portant to highlight before examining the literature on bi- months following recovery from an acute episode. Follow- polar maintenance. First, prevention trials for bipolar dis- ing this period is the continuation phase, which is defined order can be divided into 2 distinct groups: prophylaxis as months 2 through 6. During the continuation period, the and relapse prevention studies. Prophylaxis trials involve natural course of the episode is still active and discontinu- the treatment of patients who are generally considered to ing treatment results in relapse into the existing acute epi- be euthymic. Thus, these patients may have been stable for sode. After 6 months of recovery, the maintenance phase years or recently recovered from an acute depressive or begins and can be conceptualized as the time in which the manic episode. In other words, in prophylaxis studies the previous acute episode has resolved. During the mainte- patients are selected regardless of their last acute mood nance phase, the appearance of a mood episode indicates a state, and the study drug is added to assess efficacy in pre- recurrence of symptoms, i.e., a new acute episode different venting new mood episodes. In contrast, relapse preven- from the previous. To properly interpret the results of a tion involves patients in an acute episode who are treated study, we must distinguish between the continuation and openly with the study drug to short-term recovery and who maintenance phase results. For example, in an enriched- are then randomly assigned to continue active treatment design study, positive results within the first 6 months very or switch to placebo. This “enriched” study design, com- likely indicate effectiveness in relapse prevention as op- monly used in randomized controlled trials (RCTs) today, posed to true prophylactic efficacy.
is not as generalizable as the classic prophylaxis RCT de- The rationale for randomized studies is to remove the sign, as it is only applicable in the greater population to effects of confounding factors, i.e., the impact of factors those patients that begin the drug during an acute episode other than the experimental intervention that might lead to and then continue treatment after recovery.
the result.2 Randomization ensures that, except for the ex-perimental factor of interest, all known and unknown fac-tors are equally distributed in the groups studied. One canonly compare different results in the same sample if onewants to maintain the benefits of randomization, such as From the Bipolar Disorder Research Program, Cambridge the removal of confounding bias. To directly compare re- Health Alliance, Cambridge, Mass., and Department of sults from different studies would be to commit the “apples Psychiatry, Harvard Medical School, Boston, Mass. This article is derived from the teleconference “Managing and oranges” error, as the results from different studies are Bipolar Depression,” which was held June 18, 2003, and not directly comparable due to the variability of potential supported by an unrestricted educational grant fromGlaxoSmithKline. confounding factors (e.g., age, gender distribution, severity Corresponding author and reprints: S. Nassir Ghaemi, of illness). While it is logical that if drug A is shown in M.D., Cambridge Health Alliance, Department of Psychiatry,1493 Cambridge St., Cambridge MA 02139 one study to have response rates equivalent to drug B, and drug B is shown to have better efficacy than drug C in COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
Strategies for Preventing Recurrence of Bipolar Disorder Table 1. Methodological Guidelines for Maintenance Studies
of Bipolar Disordera
In a recent review of the literature on lithium,3 14 1. Continuation phase efficacy is not necessarily the same as double-blind, randomized studies of lithium in 541 pa- tients were identified in which lithium was found to be 2. “Enriched” samples may reflect relapse prevention better than true efficacious in long-term maintenance treatment of bipolar 3. Avoid the “apples and oranges” error: do not directly compare disorder. Although most of the studies were limited by a frequencies across different studies.
high dropout rate, lithium was found to be effective in re- 4. It is best to compare experimental drug with active control and ducing mania and affective morbidity associated with bi- 5. The risk of positive findings increases with the number of secondary polar disorder. Recent studies using a gradual discontinu- ation design also suggest similar efficacy. Three studies3 using a gradual discontinuation design among 1010 pa-tients have suggested efficacy with lithium.
Rapid cycling occurs in 10% to 20% of patients diag- another study, then drug A is equivalent to drug B and bet- nosed with bipolar disorder.4 These patients may be inher- ter than drug C. This logic, however, is not empirically ently treatment refractory and less responsive to prescribed valid in RCTs. To draw these conclusions, these compari- treatment when compared with patients who do not suffer sons would have to be observed in the same study. Thus, from rapid cycling.5 Between 72% and 82% of patients the ideal study design for maintenance treatment is com- who suffer from rapid cycling have shown poor response posed of 3 arms: the experimental drug, an active control, to lithium treatment,6 and it has been hypothesized that pa- tients with rapid cycling may respond better to anticonvul- In interpreting RCTs, it is also important to distinguish sant than lithium treatment. A recent meta-analysis,5 how- primary from secondary outcomes. Primary outcomes are ever, of 16 studies compared the efficacy of various mood included in the main analysis and should receive the most stabilizers in 1856 bipolar patients with and without rapid weight. Secondary outcomes are more liable to be positive cycling. All of the studies included patients who had been by chance, and thus are best seen as exploratory rather than treated for at least 4 months and had suffered from at least definitive. Often, studies are described according to the 4 recurrences of mania or depression within the previous positive findings regardless of whether the finding is a pri- year. The mean length of treatment time was 47.5 months, mary or a secondary analysis. The p value of .05, otherwise and prevalence of rapid cycling was estimated at 15.4%.
interpreted as a 5% likelihood that this result occurred by The rates of recurrence and clinical nonimprovement were chance, applies only to the primary outcome hypothesis.
more than twice as high on average in rapid cycling If more than the primary hypothesis is tested, the p value patients than patients without rapid cycling, with anticon- must be adjusted for multiple comparisons, such as with vulsants and lithium having similar efficacy. The pooled the Bonferroni correction. For example, suppose that in a recurrence rates per month were in fact lower with lithium maintenance study, the primary analysis was negative and (2.09%) than with valproate (3.63%) or lamotrigine the secondary analysis found a positive result with a p (8.5%), although there was great variability in the data.
value of .025. The Bonferroni correction for multiple com-parisons divides the p value by the number of comparisons made to adjust for any false-positive findings. The more Two studies7,8 have focused on long-term trials of dival- comparisons that are made, the smaller the p value needs to proex. Bowden and colleagues7 conducted a double-blind, be to account for any false-positive findings. If 5 compari- parallel-group, multicenter RCT comparing the efficacy of sons were made, .05 divided by 5 gives a p value of .01, divalproex, lithium, and placebo as prophylactic treatment thus rendering the p value of .025 not significant when tak- over 52 weeks. Patients meeting DSM-III-R criteria for bi- ing into account the small number of multiple comparisons.
polar depression were randomly assigned to maintenance Below, we review the literature on maintenance treat- treatment with divalproex (N = 187), lithium (N = 91), or ment of bipolar disorder through an evidence-based and placebo (N = 94). All participants were between 18 and 75 methodologically oriented perspective.
years of age, with an index manic episode as diagnosed bythe DSM-III-R, and had suffered from at least 1 other manic episode in the past 3 years. Manic episodes weredefined either as a Mania Rating Scale score of ≥ 16 or as Historically, lithium has been the medication of choice an episode requiring hospitalization. Depressive episodes when treating acute bipolar episodes and, more impor- were defined as requiring antidepressant treatment or pre- tantly, in maintenance therapy. Other agents, such as val- mature discontinuation from the study because of depres- proate, olanzapine, lamotrigine, and antidepressants, have sive symptoms. The primary outcome measure was time to also been studied recently as primary or adjunctive treat- any mood episode. Doses, which were gradually increased ments for the management of bipolar disorder.
on the basis of body weight and serum trough concentra- COPYRIGHT 2004 PHYSICIANS POSTGRADUA
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tions, were maintained at 71 to 125 µg/mL for divalproex In an olanzapine versus lithium maintenance study,13 and 0.8 to 1.2 mmol/L for lithium. The primary outcome 431 patients meeting the symptomatic remission criteria was negative: both divalproex and lithium were similar to after a 6- to 12-week, open-label, combination treatment placebo in the time to onset of another full mood episode, with both agents were then randomly assigned to one while secondary analyses suggested a potential benefit treatment. The double-blind trial lasted 52 weeks, with re- with divalproex in prevention of depressive episodes.
lapse defined as a YMRS total score ≥ 15 and/or a 21-item In another recent double-blind, randomized, mainte- HAM-D total score ≥ 15. Patients were treated with 5 to nance study8 of rapid cycling in bipolar disorder, dival- 20 mg/day of olanzapine (N = 217) or 300 to 1800 mg/day proex or lithium was administered to 61 patients over 20 of lithium (N = 214). In the primary outcome, the relapse months. Divalproex delayed relapse somewhat compared rate was slightly lower in the olanzapine-treated group with lithium, but the difference was not statistically sig- (30%) than the lithium-treated group (38.8%). Among sec- nificant. Due to the small sample size and increasing pa- ondary outcomes, olanzapine-treated patients had a lower tient dropouts over time, there was a large risk of a type II, incidence of relapse into manic episodes than lithium- treated patients (14.3% vs. 28.0%). However, both groupshad similar incidences of depression relapse. The overall dropout rate was 60.3% in 1 year, but more olanzapine- Olanzapine has been shown to be effective in treating treated patients (46.5%) than lithium-treated patients acute mania, and researchers have sought to examine the (32.7%) completed the study. High dropout rates make the long-term benefits of olanzapine treatment. Recent main- statistical comparisons difficult to interpret, but in this tenance studies have compared olanzapine directly to val- study13 the dropout rates were somewhat lower than in the proate and lithium,9 added to valproate or lithium,10 and as divalproex-olanzapine study.12 Again, the absence of a pla- monotherapy compared with placebo.11 It is important to cebo group precludes definitive interpretation of efficacy, note that the olanzapine studies did not use the ideal 3-arm although this study13 is suggestive of similar results in this treatment design (olanzapine vs. active control vs. pla- relapse-prevention design for acutely manic patients who cebo), and thus the results are not conclusive.
were initially responsive to olanzapine. These data cannot Tohen and colleagues12 studied the efficacy of olanza- be generalized to the entire population of patients with pine and divalproex in 251 patients. Participants in this double-blind study were between the ages of 18 and 75 One maintenance adjunctive treatment trial10 has been years and had a DSM-IV diagnosis of manic or mixed conducted with olanzapine. Olanzapine (N = 30) or pla- episode bipolar disorder and a baseline score of at least cebo (N = 38) was combined with either valproate or 20 on the Young Mania Rating Scale (YMRS). Patients lithium for 18 months to determine whether olanzapine were randomly assigned to olanzapine (N = 125) or dival- augmentation would reduce symptomatic relapse among proex (N = 126) for a period of 47 weeks. The initial doses bipolar patients. In the primary analysis, there was no ben- were 15 mg/day of olanzapine (mean modal dose = 16.2 efit in the olanzapine group compared with the placebo mg/day) and 750 mg/day of divalproex (mean modal group in time to a mood episode among syndromal re- dose = 1584.7 mg/day). Dose adjustments were based sponders. In one of the secondary analyses, those who on clinical response, serum concentrations, and adverse achieved complete remission for the treatment of acute events. Symptomatic remission of mania and depression manic episodes appeared to show an increase in survival was defined as an endpoint total YMRS score of 12 and a time until symptomatic recurrence was seen. Thus, in Hamilton Rating Scale for Depression (HAM-D) score terms of syndromal recurrence, there was no difference in ≤ 8. Severity of symptoms was assessed using the 11-item the total samples. In terms of symptomatic recurrence, YMRS and the 21-item HAM-D, and severity of illness however, there may have been benefit in the combination was rated on the Clinical Global Impressions scale (CGI) of olanzapine with valproate or lithium among patients for Bipolar Illness and the Positive and Negative Syn- who had complete remission of the acute mania phase.
drome Scale. In the primary outcome, time to symptom- One might then conclude that if a patient responds com- atic remission for manic and depressive symptoms be- pletely to olanzapine plus a mood stabilizer for acute ma- tween the 2 groups was similar, and the rates of remission nia and has very few manic symptoms after a month or were greater in both groups at endpoint than at 3 weeks.
two of treatment, then there might be a long-term benefit Among secondary outcomes, symptomatic and syndromal in continuation of the agent. However, the side effect dis- remission of mania was reduced significantly sooner with advantage with olanzapine treatment was weight gain, olanzapine than with divalproex. However, 84% of the with a 20% incidence of weight gain seen in the olanza- sample discontinued treatment, which suggests both treat- pine combination group versus a 2% incidence of weight ments might have been equally ineffective. Further, due to gain in the placebo combination group.
the absence of a placebo group, one cannot assess whether In the last maintenance RCT with olanzapine,11 patients were openly treated for acute mania with olanzapine and COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
Strategies for Preventing Recurrence of Bipolar Disorder then randomly assigned to long-term, double-blind, treat- primary analysis, both lithium and lamotrigine were sig- ment with olanzapine (N = 225) or placebo (N = 136).
nificantly superior to placebo in delaying time to interven- Relapse was defined as a YMRS total score ≥ 15, and/or tion for any mood episode. Median survival times were a 21-item HAM-D total score ≥ 15, and/or psychiatric 200 days for lamotrigine, 170 days for lithium, and 93 hospitalization. In the primary outcome, the majority of days for placebo. In secondary analyses, lithium was placebo-treated patients appeared to rapidly relapse within found to be statistically superior to placebo in prolonging 1 or 2 months after randomization, while time to relapse time to intervention in manic or hypomanic episodes, was significantly longer in the olanzapine-treated patients while lamotrigine was found to be superior to placebo in (p < .001). After 1 year of follow-up, relapse to an affec- prolonging the time to intervention for depressive epi- tive episode occurred in 46.7% of olanzapine-treated pa- sodes. After adjusting for the number of analyses per- tients compared with 80.1% of placebo-treated patients.
formed with the Bonferroni correction, these results would Among secondary outcomes, olanzapine-treated patients had a lower rate of relapse into manic episodes (16.4%) A similar randomized, double-blind, parallel-group when compared with placebo-treated patients (41.2%).
study15 assessed the efficacy of lamotrigine versus lithium The main benefit with olanzapine appeared to occur in the versus placebo as maintenance treatment in recently manic continuation phase (within 2 months after resolution of or hypomanic patients with bipolar I disorder. Patients had acute mania). In other words, there was rapid relapse after to be at least 18 years of age and have a DSM-IV diagnosis discontinuation of olanzapine within 2 months of recovery of bipolar I disorder. The most recent clinical interview from acute mania. Whether this continuation-phase benefit and/or mood episode must have been within the past 60 translates into long-term prophylactic benefit is unclear.
days of enrollment, and participants must have had a his-tory of at least 1 manic or hypomanic episode, and 1 addi- tional depressive episode, including mixed episode, within Lamotrigine has been studied as a maintenance treat- 3 years before study enrollment. After an open-label phase ment for bipolar I disorder, especially in patients with re- of 8 to 16 weeks, all participants who had reached a stable dose of lamotrigine while maintaining a CGI-S score ≤ 3 One randomized, double-blind, parallel-group study14 for 4 weeks (N = 175) were then eligible for the double- observed the efficacy of lithium versus lamotrigine versus blind randomization phase of this trial (lamotrigine, 59 pa- placebo as maintenance treatment for bipolar patients with tients; lithium, 46 patients; placebo, 70 patients). Similar recent depression. Participants had to be at least 18 years to the Calabrese et al. study,14 eligible patients were ran- of age and have a DSM-IV diagnosis of bipolar I disorder domly assigned to 1 of 5 treatment groups: lamotrigine, with a clinical interview or most recent mood episode oc- 100, 200, or 400 mg/day; lithium, titrated to serum levels curring within 60 days of the screening visit. Participants of 0.8 to 1.1 mEq/L; or placebo for a period of up to 19 also had to have a history of at least 1 manic or hypomanic months. Again, the primary efficacy endpoint measure episode within 3 years before study enrollment and at least was time to intervention with any other type of treatment, 1 additional depressive episode, including mixed episode, and the secondary efficacy endpoint measures were time within 3 years of enrollment. After an open-label phase of to early discontinuation; time to intervention for any 8 to 16 weeks, all participants who had reached a stable manic, hypomanic, mixed episode, or depressive episode; dose of lamotrigine and had maintained a CGI-Severity or a mean change from baseline on the MRS, HAM-D, (CGI-S) score ≤ 3 for 4 weeks (N = 463) were eligible for CGI, or GAS scales during the double-blind phase of the the double-blind, randomization phase of this trial.
Patients were randomly assigned to 1 of 5 treatment Of the 175 randomized patients, 35 patients discon- groups—lamotrigine, 50, 200, or 400 mg/day; lithium, ti- tinued due to adverse events. For these patients, the trated to serum levels of 0.8 to 1.1 mEq/L; or placebo—for mean duration of time spent in the study was 300 days a period of 18 months, with 221 patients in the lamotrigine (SD = 115; range, 136–582 days). Among the rest of the group, 121 in the lithium group, and 121 in the placebo randomized group, excluding natural endpoints, discon- group.14 The primary efficacy endpoint measure was time tinuation rates were higher in the lithium group (24%) due to intervention with any other type of treatment, and the to adverse events as compared with the other 2 groups (la- secondary efficacy endpoint measure was time to interven- motrigine or placebo) and in the lamotrigine group (7%) tion for any manic, hypomanic, or depressive episode or a for withdrawal of consent. Both lithium and lamotrigine mean change from baseline according to the HAM-D, Ma- were superior to placebo in delaying time to intervention nia Rating Scale (MRS), CGI-S, or Global Assessment for any mood episode (p = .003 and p = .02, respectively) Scale (GAS) scores. The rates of discontinuation classified and did not differ from each other for this variable. Me- by reason were similar across treatment groups, although dian survival times were 85 days for lamotrigine, 101 days lithium tended to have a higher rate of discontinuation due for lithium, and 58 days for placebo. In secondary analy- to adverse effects than the other 2 treatment groups. In the ses, lithium was superior to placebo at delaying time to a COPYRIGHT 2004 PHYSICIANS POSTGRADUA
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Table 2. Randomized Clinical Trials of Long-Term Antidepressant Treatment in Bipolar Disordersa
Efficacy: Li = IMIMania: IMI > Li (women) aReprinted with permission from Ghaemi et al.17Abbreviations: BP = bipolar disorder (type I or II); BUP = bupropion; DMI = desipramine HCl; FLX = fluoxetine; IMI = imipramine HCl; Li = lithium carbonate; PBO = placebo; RDC = Research Diagnostic Criteria; UP = unipolar depression. Symbols: > = more effective than,>> = much more effective than. Efficacy results are for bipolar depressive symptoms or episodes unless stated otherwise.
manic, hypomanic, or mixed episode, whereas lamotrigine On the risk side, there is some evidence18,19 of potential was superior to placebo in delaying time to a depressive risk of rapid cycling or cycle acceleration with antidepres- episode. These secondary analyses, however, would not be sant treatment. Rapid cycling appears to happen in about statistically significant after the Bonferroni correction.
20% to 25% of patients treated with tricyclic antidepres- Another study16 did not find lamotrigine monotherapy sants (TCAs).18 In the only available observational data19 to be effective in the treatment of patients suffering from comparing newer antidepressants and older antidepres- bipolar disorder with rapid cycling. A total of 324 patients, sants, we found that rates of rapid cycling in bipolar disor- who were either euthymic or experiencing a mood epi- der were found to be similar between TCAs and selective sode, entered an open-label preliminary phase. This phase serotonin reuptake inhibitors (SSRIs).
consisted of a 6-week titration period of lamotrigine to a Data17,20 on antidepressants in the long-term treatment target dose of 200 mg/day. All participants were 18 years of bipolar disorder suggest lack of efficacy. A review of re- or older with a DSM-IV diagnosis of bipolar I or II search17,20–26 on the use for long-term treatment of bipolar with rapid cycling. After 6 weeks, 182 patients were then disorder found 7 blinded controlled trials that showed anti- randomly assigned to lamotrigine or placebo for a 26- depressant monotherapy or adjunctive treatment as inef- week, double-blind treatment phase. The primary outcome fective (Table 2). For example, one study20 randomly as- measure was the time to additional pharmacotherapy signed 75 patients who met the Research Diagnostic for emerging symptoms. Secondary efficacy measures in- Criteria (RDC) for bipolar disorder to either a lithium (300 cluded time to premature discontinuation, the percentage mg/day) plus placebo group (N = 38) or a lithium (300 of patients who relapsed after 6 months, and changes in mg/day) plus imipramine (100 to 150 mg/day) group the GAS and CGI-S scores. In the primary analysis, no dif- (N = 37). Patients were required to have experienced epi- ference was found between the lamotrigine- and placebo- sodes of mania as well as major or minor depression, treated groups in regard to time to additional pharmaco- maintained euthymia for at least 6 weeks while receiving therapy. Among secondary analyses, some benefit was lithium treatment, be 18 to 65 years old, and have no coex- observed with lamotrigine in patients with type II bipolar isting medical illness. Outcome measures included type of disorder. As a secondary finding, however, this result is relapse, time to relapse, and subsequent illness. Thirty-two percent (N = 12) of lithium-imipramine–treated patientsand 24% (N = 9) of lithium-placebo–treated patients re- lapsed. The lithium-imipramine group tended to have Long-term treatment of bipolar disorder with antide- more manic relapses and did not have fewer depressive re- pressants has to be considered in terms of the risk-benefit lapses than the lithium-placebo group.
ratio. On the benefit side, adjunctive antidepressant treat- The question has been raised whether discontinuation ment may improve current acute depression symptoms in of antidepressants produces increased risk of depressive the short-term. In the long-term, however, for prevention relapse. In one observational study,27 a total of 84 patients of future episodes, studies17,20 suggest that antidepressants with bipolar disorder were prescribed an antidepressant as a cotherapy with a mood stabilizer. After 6 months, 43 COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
Strategies for Preventing Recurrence of Bipolar Disorder patients discontinued the antidepressant treatment, while less overall affective morbidity after adjusting for the po- the other 41 patients continued the antidepressant treat- tential confounders (β = –0.40, 95% CI = –2.21 to 1.42).
ment for another 6 months. A significantly shorter time Further, stratification by rapid cycling suggests that over- to depressive relapse was found among patients in the all affective morbidity is decreased in both rapid cyclers discontinuation group when compared to patients in the and non–rapid cyclers. In contrast to the above observa- continuation group. The discontinuation group also expe- tional study,27 a Cox regression analysis suggests no in- rienced a significantly shorter period of euthymia before creased risk of relapse with antidepressant discontinu- relapse than the continuation group.
ation (hazard ratio [HR] = 1.21, 95% CI = 0.37 to 3.97) As with any observational study, the primary question compared to antidepressant continuation.
that needs to be raised is whether there was a risk ofconfounding bias, how this risk was assessed, and what attempts were made to control or adjust for suchpotential confounding effects. In randomized studies17,20 Unfortunately, medication efficacy frequently does not of sufficient size, confounding effects are removed by the translate into functional recovery. Consequently, there is randomized study design. However, in observational, growing interest in the use of psychotherapy to enhance nonrandomized studies such as this one,27 possible con- remission and functional status. In 13 randomized studies founding effects can only be assessed in 2 ways: stratifi- among 896 patients, increased remission rates and de- cation or regression analysis. In the case of stratification, creased relapse rates were found when medication was a relevant variable, such as rapid cycling, would be cho- sen, and the risks of depressive relapse would be assessed The types of psychotherapy used in bipolar mainte- only in those with rapid cycling and in those without nance are primarily psychoeducational and cognitive- rapid cycling. If there is no difference in the 2 groups, behavioral psychotherapies, although research has been then one could infer that rapid cycling did not have a con- done with family-based29 and interpersonal30 therapies.
founding effect. In regression analyses, one could include Evidence from psychotherapy relapse prevention data factors such as rapid cycling in mathematical models for demonstrates that some forms of psychotherapy may be regression analysis (in the case of survival data, Cox re- better at preventing depressive recurrence31,32 while others gression). This study did not examine any variables for may be better at preventing manic recurrence.33,34 potential confounding effects; even though a Cox propor-tional hazards regression was conducted, no potential confounding variables were included in the regression Studies have shown that cognitive-behavioral therapy model. The major potential confounders of interest are (CBT) is effective in preventing bipolar depressive epi- clinical factors (rapid cycling status, number of previous sodes but not manic episodes.31,34 One possible reason is episodes, other measures of severity of illness, age, and that cognitive strategies focus on identification of auto- gender) and the general impact of “confounding by indi- matic thought process, challenging negative thought pat- cation,” which refers to the factors influencing the non- terns and confronting barriers to treatment.
random decisions of clinicians at the beginning of the Scott31 explored the efficacy of cognitive therapy study. As a consequence of these limitations, one cannot among patients with bipolar disorder who were taking be certain of the validity of the results of this observa- medication. Forty-two participants were randomly placed in either a cognitive therapy (CT) group or a 6-month In contrast, we have been conducting a randomized waiting list control (WLC) group. All participants were study28 in order to avoid many of these limitations. In this over 18 years of age with a lifetime diagnosis of bipolar I open-randomized design, patients who had responded or II disorder and had experienced 1 or more affective dis- to a mood stabilizer plus an antidepressant for acute bi- orders in the last 2 years. Patients in the CT group were polar depression were assigned to either discontinue required to participate in a maximum of twenty-five (short-term group) or to continue (long-term group) their 45-minute sessions for a period of 6 months, and both current antidepressant treatment following recovery for groups continued to receive any previously prescribed 2 months. The primary outcome was the total affective medications. The CT group showed greater improvements morbidity, defined as the absolute sum of the scaled in symptoms and functioning as measured by the Beck manic and depressive symptoms followed on a clinical Depression Inventory, Internal State Scale, and Global monitoring form (0 = no symptoms, 1–6 = subsyndromal Assessment of Functioning than patients in the WLC mood episode, > 6 = syndromal mood episode). An in- terim analysis of the data at the halfway point of this A small pilot study32 compared the efficacy of CBT 5-year study has been conducted. A repeated measures in bipolar and unipolar depressed patients. Eleven par- linear regression of overall affective morbidity suggests ticipants with bipolar disorder were matched to 11 par- that the antidepressant discontinuation group had slightly ticipants with unipolar depression. All participants were COPYRIGHT 2004 PHYSICIANS POSTGRADUA
TE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
between the ages of 18 and 65 years, met the RDC for bipolar I or II disorder (depressed) or unipolar depression,and had a score > 14 on the 17-item HAM-D. Patients with Lithium has the greatest quantity and quality of data bipolar depression were also treated with lithium or an to support its use as a maintenance treatment in bipolar anticonvulsant mood stabilizer. Participants completed an disorder. Anticonvulsants, such as divalproex, and atypi- individual CBT course after an initial assessment and 20 cal antipsychotics, such as olanzapine, are also useful, es- weeks of CBT based on standard protocol with modified pecially among patients suffering from mania. Depressive specific techniques for the bipolar patients. Bipolar pa- relapse, however, is still a concern. Unfortunately, long- tients showed a mean reduction on HAM-D score of over term antidepressant use does not appear to be a simple 50%, which was comparable to the reduction seen in pa- solution. Standard antidepressants appear to be ineffective at best and potentially harmful at worst. Lamotrigine mayhave some specific benefit for depressive symptoms.
Polypharmacy, however, is often a common thread among Psychoeducation may help patients to identify the early bipolar disorder patients. Long-term monotherapy with symptoms of relapse and seek treatment before relapse ac- mood stabilizers has been noted in less than one third of tually occurs. Studies33,34 have found that psychoeducation bipolar patients.35 Thus, polypharmacy with mood stabi- is particularly beneficial in the reduction of manic symp- lizers primarily, while using antidepressants infrequently, toms. Psychoeducation may also improve the long-term appears to be the most effective approach to treating bipolar disorder. Psychotherapies, primarily psychoedu- A recent study33 of group psychoeducation was par- cational and cognitive-behavioral, have demonstrated tially aimed at trying to improve insight in patients with promise in enhancing remission and functional status in bipolar disorder, and it showed efficacy in improving long-term outcome. A total of 120 patients were random-ized into 2, single-blind, parallel groups (N = 60 each) for Drug names: bupropion (Wellbutrin and others), divalproex 20 weeks of treatment and 2 years of follow-up study.
(Depakote), imipramine (Tofranil and others), lamotrigine (Lamictal),lithium (Eskalith, Lithobid, and others), olanzapine (Zyprexa).
In the treatment phase, all patients received usual psy- chiatric care with standard pharmacologic treatment. All Disclosure of off-label usage: The authors have determined that, to patients were seen by 2 psychiatrists and were advised to the best of their knowledge, lithium, bupropion, and lamotrigine are go to the bipolar disorder program center whenever they not approved by the U.S. Food and Drug Administration for the treat-ment of bipolar depression; and divalproex is not approved for the felt any change in mood or experienced other problems.
maintenance treatment of bipolar disorder.
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with lithium or valproate for relapse prevention of bipolar disorder: COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC. COPYRIGHT 2004 PHYSICIANS POSTGRADUATE PRESS, INC.
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http://www.springerlink.com/content/u4033x6446t78544/?MUD=MP Seguridad y eficacia de la terapia con carvedilol en pacientes con cardiomiopatía dilatada secundaria a distrofia muscular J. Rodas, R. Margossian, Darras BT, SD Colán, KJ Jenkins, T. Geva y AJ Powell Recibido: 14 de junio de 2007 / Aceptado: 10 julio 2007 J. Rodas, R. Margossian, SD Colán, KJ Jenkins, T. Geva y AJ Powell Departamento