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Even though there has been a recent proliferation of randomized controlled trial (RCT) data in the treatment of bipolar disorder, as well as the publication of 2 new US treatment guidelines over the past year -- the updated Texas Implementation of Medication Algorithms (TIMA) bipolar algorithm and the Expert Consensus Series (ECS) bipolar guidelines[1,2] -- the treatment of the disorder remains frustrating for many patients and clinicians, and the role of guidelines in shaping decision making is still uncertain. In this column, I highlight areas of particular debate for clinicians, review the recent evidence that has bearing on this debate, and address how some questions can be answered by the updated TIMA and ECS guidelines.

Both new guidelines aim to summarize evidence-based interventions, and they both utilize expert opinion in addressing those areas where there had been inconsistencies or inadequacies in the data. However, there are important differences between them and they represent 2 different approaches: where ECS uses a survey methodology in which "experts" are presented with clinical scenarios, TIMA relies on a panel of experts reviewing evidence tables to explicitly achieve consensus.

Depression and the Role of Standard Antidepressants

With all the attention that has been paid to the debate over the use of standard antidepressants in bipolar disorder,[3] remarkably little evidence exists for the development of true "evidence-based' guidelines.[4] There are really 2 basic questions about antidepressants: first, are they an effective treatment when added to other medications such as lithium or valproate, and second, are they safe when administered in this way? A number of rather small studies, most of them flawed in some way, have addressed the question of benefit; in general, it has been difficult to show additive benefit when antidepressants are used as an additive treatment.[4,5] A notable exception is an industry-supported study of olanzapine, administered with and without fluoxetine in which the combination was superior to olanzapine monotherapy.[6] While rarely discussed in this way, this trial could be construed as evidence of a benefit for bipolar patients when an antidepressant is used in conjunction with an antimanic.

On the other side of the equation, older studies of tricyclic antidepressants or monoamine oxidase inhibitors that were generally administered without mood-stabilizing medications suggested that antidepressant treatment could be harmful, increasing the risk of manic switch or cycling.[7,8] Whether this is also the case with newer antidepressants is less clear; certainly this risk, if present, appears to be much lower, at least when these agents are combined with lithium or olanzapine.[5,6]

In TIMA, antidepressants are to be considered only after exhausting other options, including traditional mood stabilizers, lamotrigine, quetiapine, or the olanzapine-fluoxetine combination. (Notably, only a minority of the TIMA panelists apparently favored early use of antidepressants.[1]) The decision to favor lamotrigine seems odd, given that a published 'positive' trial in bipolar depression was not significant on its primary outcome measure,[9] whereas the trial for olanzapine-fluoxetine,[6] and that for quetiapine[10] did demonstrate clear evidence of efficacy. These findings have since been replicated in a second large trial, not yet published.

In the ECS guideline, antidepressants do slightly better: for severe depressive episodes they are considered a reasonable first-line option (in combination with lithium), and an alternative option for less severe episodes. For subjects with any history of antidepressant-induced mania or cycling, however, they are not advised. Here, the approach -- while less evidence-based than TIMA -- probably fits better with most clinicians' practice, though, of course, this does not necessarily imply that it is correct.

Of interest, in both guidelines, lithium shares first-line status with other, newer interventions. Data continues to accumulate suggesting that lithium may help to reduce the substantial suicide risk in bipolar disorder. For example, one important epidemiologic study using patients drawn from 2 large health-maintenance organizations suggested that with lithium, there was a reduction in risk of suicide attempts or completions.[11] In an RCT of schizophrenia patients, only clozapine has been shown to reduce risk of suicidality.[12] A similar trial with lithium would help to settle the question. Still, what data exists would seem to more strongly support the use of lithium in bipolar depression as well as during maintenance.

Mania and the Use of Atypical Antipsychotics

Now that all of the atypical antipsychotics have joined clozapine in receiving US Food and Drug Administration approval for the treatment of mania, an obvious next question is where they stand relative to each other and to the older antimanics, such as lithium and valproate. Are they like the selective serotonin reuptake inhibitors (SSRIs) in major depression, which differ somewhat in adverse effect profiles but appear to have very similar efficacy? In terms of their mechanism of action, these agents certainly show more variation than the SSRIs. The recent CATIE trial in schizophrenia[13] suggested that olanzapine might be both more effective and more risky metabolically than the other atypicals; otherwise, the class as a whole performed similarly. Unfortunately, no such trial exists in bipolar disorder, so head-to-head comparisons of agents are difficult. One meta-analysis suggests that, at least in terms of efficacy vs placebo, the atypical antipsychotics perform similarly.[14] Two head-to-head valproate vs olanzapine studies suggest similar efficacy but differences in tolerability.[15,16]

Perhaps presciently, the initial TIMA algorithms had singled out olanzapine, limiting it to second-line (actually, "1B") treatment of mania because of the risk of weight gain and other metabolic effects, which can be apparent even early in treatment.[17] Otherwise, the updated algorithms suggest that any of the atypical antipsychotics, as well as lithium and valproate, are reasonable first-line interventions in manic patients.

The ECS guidelines likewise support either lithium or valproate, or atypical antipsychotics, in the initial treatment of mania. While TIMA advises monotherapy as first-line treatment, ECS also supports combination therapy (an atypical antipsychotic with a traditional mood stabilizer) as a reasonable first-line intervention in most cases.

Because ECS was developed before all of the RCT data for aripiprazole or ziprasidone were available, it favors the other atypical antipsychotics, but makes little distinction between them.

Maintenance and the Role of Combination Therapy

With positive results in RCTs, lamotrigine, olanzapine, and aripiprazole have all joined lithium as a treatment in the prevention of recurrence of bipolar disorder.[18,19] With all of these newer options available, it might seem as though the problem of maintenance treatment has been solved. In fact, however, in an examination of nearly 900 patients given "best-practice" treatment, it was found that about 50% experienced at least 1 recurrence during a period of up to 2 years of prospective follow-up.[20] This is generally consistent with data from randomized trials: while newer agents are certainly better than placebo, recurrence rates remain high.

Rather than develop specific algorithms, TIMA ranks interventions based on quality of evidence. It was shown that lithium and valproate were favored, with lamotrigine a possibility in patients without frequent, recent, or severe mania, on the basis of 2 trials in which it was superior to placebo in preventing depressive recurrence.[18] Olanzapine showed perhaps the greatest evidence of efficacy in prevention of manic recurrence, but the same metabolic concerns that led the panel to rate it as an alternate in mania led them to do so during the maintenance phase.

Valproate continues to be considered a first-line maintenance agent, though the evidence in its favor could be considered equivocal: It failed to separate from placebo on time to recurrence in one study, though lithium performed similarly.[21] Its relapse or recurrence rates were similar to those seen with olanzapine in another study.[22] However, in a recent study, important as the first placebo-controlled trial in bipolar patients with a comorbid alcohol use disorder, it showed clear evidence of efficacy.[23]

Although both TIMA and ECS generally support the idea that effective acute interventions should be continued, the ECS guidelines give much more attention to maintenance and attempt to address a number of clinical circumstances based on treatment of the acute episode. The fact that there is an indefinite treatment period with the atypical antipsychotics is a source of discomfort for many doctors, with 82% of experts advising that they be discontinued after a mean of 20 weeks. Similarly, despite the support of antidepressant use acutely, the majority (70%-90%, depending on the precise scenario) of experts support discontinuing antidepressants as an additive therapy after approximately 6 months.

Both TIMA and ECS highlight 2 shortcomings in our understanding of the long-term approach to bipolar disorder. First, little real data exist to guide the decision to continue or discontinue acute interventions, and particularly the timing of such a decision. Second, despite the relatively poor outcomes with maintenance monotherapy, we know little about the benefit of combination therapy. Tohen and colleagues[24] provide the one exception with their study showing the benefit of combination olanzapine with lithium or valproate therapy.


Although recent trials suggest efficacy for several newer agents in the treatment of bipolar disorder, data remain limited on how these agents can best be integrated into clinical practice. The ECS and TIMA guidelines provide complementary syntheses of data and expert opinion. From a clinician's perspective, both can be helpful in summarizing reasonable approaches to various stages of illness. The differences between them highlight the need for clinicians to consider the needs of the individual patient, to stay abreast of new data as it appears, and to recognize that in many cases there is more than one reasonable approach. Guidelines are just that: they are intended to assist, rather than replace, clinical judgment.


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