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The effect size and least squares mean difference in bipolar II disorder was larger than in bipolar I disor-
der, but the confidence interval around the mean was much larger too, suggesting more uncertainty
about the actual size of the effect.

The evidence base informing the treatment of bipolar II disorder is remarkably bare, but the treatment of
bipolar disorder as a whole goes on without it. Data from the 1997–2016 National Ambulatory Medical
Care Surveys (NAMCS) suggest remarkable changes in prescribing among psychiatrists over that period
(10). The use of mood stabilizers (e.g., lithium and approved anticonvulsants such as lamotrigine and
valproate) declined across bipolar disorder from 62.3% of visits in the 1997–2000 period to only 26.4% of
visits in the 2013–2016 period, while antipsychotic prescribing increased fourfold, from 12.4% of visits in
1997–2000 to 51.4% of visits in 2013–2016. Remarkably, antidepressants continue to be prescribed in
the absence of any antimanic medications in 1 in 6 visits but also in 57.5% of visits in the 2013–2016 pe-
riod of NAMCS overall. Clinicians are clearly using them often in bipolar disorder despite the lack of evi-
dence that they are effective for bipolar depression (other than the limited data for fluoxetine combined
with olanzapine in bipolar I disorder) and with the possibility that they destabilize patient course (11). But
because there are so few studies of antidepressants in well-characterized samples with bipolar II disorder,
our understanding of the role of standard antidepressants in this subtype of bipolar disorder is poor. The
2018 guidelines issued by the Canadian Network for Mood and Anxiety Treatments and the International
Society for Bipolar Disorders for the mangement of patients with bipolar disorder make no first-line rec-
ommendations for the use of antidepressants in bipolar II disorder because of the absence of placebo-
controlled trials of acute depression in the disorder, but they do not counsel strongly against their use
(1). This absence of trial data for antidepressants (a potentially safe treatment) in the acute treatment of
depression in bipolar II disorder is one of the two biggest gaps in evidence; the other is the sheer ab-
sence of randomized trial evidence for the pharmacological maintenance treatment of bipolar II disorder.
Other than quetiapine, for which a statistically significant effect was found in favor of drug compared
with placebo in some (but not all) short-term trials of depression in bipolar II disorder, there is little quali-
ty evidence on which clinicians can draw in treating this common problem, even if efforts to study psy-
chotherapy for it have been bravely attempted (12, 13).

While it is welcome to have data for a new drug as a treatment for bipolar disorder, the results of this
study should be interpreted cautiously. The study duration was only 6 weeks, and short-term data are dif-
ficult to use to guide treatment beyond that period, especially from the perspective of safety and tolera-
bility. The safety data from patients with schizophrenia, a more extensively studied group exposed to lu-
mateperone, may not be predictive of the data that one might later see from patients with bipolar disor-
der, as the baseline medical illnesses, effects of prior treatments with antipsychotics, comorbidities such
as tobacco smoking, and social circumstances differ between these patient populations. The paucity of
long-term data on the safety and efficacy of lumateperone (as with other antipsychotics) compared with
other medications and treatments in bipolar disorder, an illness across the lifespan, complicates its rec-
ommendation. The use of monotherapies in bipolar disorder (even with an antipsychotic drug) is rare, so
the generalizability of these findings to practice is also not known (1, 8). Nevertheless, research into new
treatments for patients in depressive episodes of bipolar disorder (and especially bipolar II disorder) is
always welcome, even if more pointed questions—for example, what do we really do to prevent the life-
long suffering in bipolar II disorder?—remain incompletely answered.

Editorial Originally Published in the American Journal of Psychiatry. Full article and citations can be found
here.

To comment or respond to the editorial Click Here.

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