In the open stabilization stage, the incidence of any rash was 0.8% (11/1,305), which included two noteworthy rashes. One was a case of Stevens-Johnson syndrome classified as nonserious because it did not require hospitalization, and the other was a case of severe maculopapular nonpruritic facial rash classified as serious because it did require hospitalization. Both resolved uneventfully with lamotrigine discontinuation. In the randomized controlled stage, the incidence of rash was 5% with lamotrigine, 7% with lithium, and 5% with placebo.There are limited data regarding baseline markers of lamotrigine maintenance response. Baseline markers of lamotrigine compared with lithium response appear in some ways overlapping and in other ways complementary.In a post hoc analysis of the lamotrigine maintenance registration studies, in 280 patients taking lamotrigine, index mixed episodes and having 3 or more depressions in the prior 2 years increased the risk of relapse (Ketter et al. 2003). Index mixed episodes also tended to predict relapse for patients taking placebo (n=191), whereas illness onset before age 20 years predicted relapse for patients taking lithium (n=167).Another study assessed 164 subjects from 21 families of probands with bipolar I disorder or bipolar II disorder who had maintenance treatment responses to lamotrigine (n=7) or lithium (n=14) (Passmore et al. 2003). The probands differed with respect to clinical course (rapid cycling in the lamotrigine responder group, episodic in the lithium responder group) and comorbidity (panic attacks and substance abuse in the lamotrigine responder group). The relatives of lamotrigine responders had higher prevalence of schizoaffective disorder, major depression, and panic attacks, whereas relatives of lithium responders had significantly higher risk of having bipolar disorder.The U.S. prescribing information for lamotrigine includes a boxed warning regarding the risk of serious rashes requiring hospitalization, which have included Stevens-Johnson syndrome, in 0.08% and 0.13% of adult mood disorder patients receiving monotherapy and adjunctive therapy, respectively. In mid2008 the FDA released an alert regarding increased risk of suicidality (suicidal behavior or ideation) in patients with epilepsy as well as psychiatric disorders for eleven anticonvulsants (including lamotrigine). Lamotrigine can cause CNS (headache, somnolence, insomnia, dizziness, tremor) and gastrointestinal (nausea, diarrhea) (Bowden et al. 2003; Calabrese et al. 1999, 2000, 2003) adverse effects. In most instances these problems attenuate or resolve with time or lamotrigine dosage adjustment, but occasionally patients may require lamotrigine discontinuation. Indeed, in view of its generally very good tolerability, clinicians and patients may prefer lamotrigine compared with other longerterm treatment options.Lamotrigine dosage is initially titrated very slowly to decrease the risk of rash. When lamotrigine is given without valproate, the prescribing information recommends starting lamotrigine at 25 mg/day for 2 weeks, then increasing to 50 mg/day for the next 2 weeks, then increasing to 100 mg/day for 1 week, and then increasing to 200 mg/day in a single daily dose, with dosages exceeding 200 mg/day not recommended unless concurrent hormonal contraceptives (which decrease serum lamotrigine concentrations) are administered (Physicians' Desk Reference 2008). The FDA did not recommend dosages over 200 mg/day because in the registration trials 400 mg/day, although effective, was no more effective than 200 mg/day. Nevertheless, even in the absence of hormonal contraceptive, selected patients may benefit from further gradual lamotrigine titration to final dosages as high as 500 mg/day. Even more gradual titration, starting with 25 mg/day for 2 weeks, then increasing to 50 mg/day for the next 2 weeks, and then increasing as necessary and tolerated weekly by 25 mg/day, may further decrease the risk of rash (Ketter et al. 2005). When lamotrigine is added to valproate (which doubles serum lamotrigine concentrations), the previous recommended doses are halved, and when lamotrigine is given with carbamazepine (which halves serum lamotrigine concentrations), these recommended doses may be doubled. Additional information regarding lamotrigine is provided in Chapter 13 of this volume.In summary, lamotrigine is a newer bipolar disorder maintenance treatment option with a novel pharmacological profile in that it is uncommonly well tolerated and provides more robust prevention of depression compared with mania, although it lacks an acute bipolar disorder indication. Clinicians and patients may deem this agent to have superior tolerability compared with other mood stabilizers such as divalproex as well as compared with antipsychotics and thus be an attractive treatment option.

Second-Generation AntipsychoticsSecond-generation antipsychotics are commonly used in acute mania and increasingly used for other aspects of the management of bipolar disorders, including longer-term therapy.

OlanzapineIn 2004, olanzapine became the third medication approved by the FDA for the longer-term treatment of bipolar disorders. This was a significant milestone be-cause in the past antipsychotics were considered adjuncts for the acute treatment phase rather than longer-term treatments. The U.S. prescribing information for olanzapine states the following in the Indication section:The benefit of maintaining bipolar patients on monotherapy with oral [olanzapine] after achieving a responder status for an average duration of two weeks was demonstrated in a controlled trial. The physician who elects to use [olanzapine] for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.

Thus, the information appeared to more resemble the continuation treatment phase than the maintenance treatment phase.The olanzapine longer-term treatment registration trial was a multicenter, randomized, double-blind, placebo-controlled study of patients with bipolar I disorder with a recent manic or mixed episode (Tohen et al. 2006). Olanzapine was superior to placebo on the time-to-event-based primary outcome measure (time to symptomatic relapse into any episode) (Figure 8-8, left), and on the three polarity-specific time-to-event-based secondary outcome measures (time to symptomatic relapse into 1) manic episode, 2) depressive episode, and 3) mixed episode). The brief period of stability prior to randomization and the early very rapid (exponential) decline in the proportion of patients remaining well (Figure 8-8, left) raised the possibility that patients were relapsing into the index episode and that the study involved a substantial continuation treatment phase component. Excluding any relapses during the first 8 weeks in part addressed such concerns, yielding a more gradual (linear) decline in the proportion of patients remaining well (Figure 8-8, right), with olanzapine still being superior to placebo on the time to symptomatic relapse into any episode, consistent with the study also having a maintenance treatment phase component.Olanzapine appeared to have preventive efficacy in a broad spectrum of patients. Thus, subgroup analyses revealed that time to symptomatic relapse was longer with olanzapine compared with placebo in patients with both manic and mixed index episodes, both psychotic and nonpsychotic index episodes, and with and without rapid cycling. Indeed, none of these factors appeared to influence time to relapse.On additional secondary event-based outcome measures (i.e., relapse rates), the findings were less robust but had the same pattern. Olanzapine was superior to placebo for overall episode prevention (NNT=3), with the benefit driven by mania/mixed episode prevention (NNT=5) (Figure 8-9, black bars). Olanza-

FIGURE 88.Comparison of 12-month double-blind olanzapine monotherapy versus placebo maintenance.Olanzapine compared with placebo after manic/mixed episodes was superior in the time-to-eventbased analysis for overall episode prevention. Patients were stabilized on open olanzapine before randomization (mean 16.3 days). The relapse criteria were hospitalization or Young Mania Rating Scale or Hamilton Rating Scale for Depression2115. (Left) Note the rapid (exponential) decrease in probability of remaining well (particularly for the placebo group), resembling therelapse" pattern in Figure 82. (Right) Note the gradual (more linear) decrease in probability of remaining well, resembling therecurrence" pattern in Figure 82.Source. Adapted and reproduced from Tohen M, Calabrese JR, Sachs GS, et al. Randomized, Placebo-Controlled Trial of Olanzapine as Maintenance Therapy in Patients With Bipolar I Disorder Responding to Acute Treatment With Olanzapine. American Journal of Psychiatry 163:247256, 2006. Used with permission.

FIGURE 89. Comparison of 12-month double-blind olanzapine monotherapy versus placebo maintenance, numbers needed to treat (NNT), and relapse rates.

Olanzapine monotherapy (black bars) compared with placebo monotherapy (white bars) after manic/mixed episodes was superior in the time-to-eventbased analyses for overall, depressive, and manic/mixed prevention, but in the event-based analysis in this figure failed to attain significance for prevention of depressive relapse. ***P