Page 8 - Jan_Feb 2022 Newsletter.pub

Slowly Working Toward More Treatments for Depression in

Bipolar II Disorder

Michael J. Ostacher, M.D., M.P.H.

There is undoubtedly a need for better well-studied treatments for major de-
pressive episodes in patients with bipolar disorder. This is true not only for peo-
ple with bipolar I disorder but, even more importantly, for patients with bipolar
II disorder—a disorder with a single compound approved by the U.S. Food and
Drug Administration (FDA) for acute treatment only (quetiapine, both immediate
release and extended release) and with little other quality data to drive treat-
ment decisions in the clinic. But both bipolar I and II disorders are, for the vast
majority of people, lifelong and chronically relapsing conditions, and the lack of
longitudinal data to guide care for the depressive phase of the illness leaves
many patients with treatment guided by anecdotal evidence, evidence of low
quality, and expert opinion rather than with much certainty (1).

The study published in this issue by Calabrese et al. (2) of a multicenter trial of
a single dose of lumateperone, a butyrophenone atypical antipsychotic, conducted by Intra-Cellular
Therapies, sheds a limited amount of light on this very dark problem. In this study, 377 analyzable sub-
jects with bipolar I (N=301) or II (N=76) disorder and a current major depressive episode were randomly
assigned to receive lumateperone or placebo for 6 weeks. Using a mixed-effects model for repeated
measures, the authors found a greater improvement with study drug on the Montgomery-Åsberg De-
pression Rating Scale (−4.6 points, 95% CI=−6.34, −2.83) over the short treatment period. The drug pro-
vided benefit for both patients with bipolar I and bipolar II disorder. (An earlier study of 554 patients
with bipolar I and II disorder with depression comparing two dosages [28 mg/day and 42 mg/day] with
placebo did not meet its prespecified outcome measures for either dosage [with results that remain both
unposted to ClinicalTrials.gov and unpublished]. A third study, of a 42-mg/day dosage, is ongoing [3–
5].)

The increased but still modest rates of reported side effects with lumateperone compared with placebo
raise the question of ascertainment bias and placebo unblinding, with somnolence (8.5% versus 1.1%)
and nausea (6.4% versus 2.1%) possibly leading to a larger effect than might be seen if an active placebo
were used (6). Whether lumateperone will ultimately reach the bar for FDA approval remains to be seen,
and clinicians may be still be tempted to use it in their patients; whether they should or not remains un-
clear until all the studies are completed and the data presented.

There are some concerns about the study, especially with regard to bipolar II disorder, that merit discus-
sion. First, the study population (which is more than 90% white and predominantly from outside the
United States) was clinically diagnosed with bipolar disorder, leaving the accuracy of the bipolar II disor-
der diagnosis less than certain because of the difficulty diagnosing hypomania retrospectively (7). Even
as bipolar I disorder is difficult to diagnose retrospectively without the presence of a clear index manic
episode (requiring hospitalization, for example, or present with psychotic symptoms), it is even more
difficult to accurately diagnose the hypomanic episodes required for the diagnosis of bipolar II disorder,
so the lack of systematic diagnosis of bipolar II disorder is problematic (8). Second, the sample of study
subjects diagnosed with bipolar II disorder and analyzed in this study is quite small—38 each in the ac-
tive drug and placebo arms—making extrapolation of these data to a clinical population problematic (9).

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NORTHERN CALIFORNIA PSYCHIATRIC SOCIETY Page 8 JANUARY/FEBRUARY 2022