Depression in
bipolar disorder (BD) patients presents major clinical challenges. As the predominant psychopathology even in treated BD, depression is associated not only with excess morbidity, but also mortality from co-occurring general-medical disorders and high suicide risk. In BD, risks for medical disorders including diabetes or
metabolic syndrome, and cardiovascular disorders, and associated mortality rates are several-times above those for the general population or with other
psychiatric disorders. The SMR for suicide with BD reaches 20-times above general-population rates, and exceeds rates with other major
psychiatric disorders. In BD, suicide is strongly associated with mixed (agitated-dysphoric) and depressive phases, time depressed, and hospitalization.
Lithium may reduce suicide risk in BD;
clozapine and
ketamine require further testing. Treatment of
bipolar depression is far less well investigated than
unipolar depression, particularly for long-term prophylaxis. Short-term efficacy of
antidepressants for
bipolar depression remains controversial and they risk clinical worsening, especially in mixed states and with rapid-cycling. Evidence of efficacy of
lithium and
anticonvulsants for
bipolar depression is very limited;
lamotrigine has long-term benefit, but
valproate and
carbamazepine are inadequately tested and carry high teratogenic risks. Evidence is emerging of short-term efficacy of several modern
antipsychotics (including
cariprazine,
lurasidone,
olanzapine-
fluoxetine, and
quetiapine) for
bipolar depression, including with mixed features, though they risk adverse metabolic and neurological effects.