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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.<\/jats:p>","DOI":"10.1186\/s40345-019-0160-1","type":"journal-article","created":{"date-parts":[[2020,1,5]],"date-time":"2020-01-05T19:08:46Z","timestamp":1578251326000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":209,"title":["Bipolar depression: a major unsolved challenge"],"prefix":"10.1186","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9718-8211","authenticated-orcid":false,"given":"Ross J.","family":"Baldessarini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gustavo H.","family":"V\u00e1zquez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Tondo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,6]]},"reference":[{"issue":"6","key":"160_CR1","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1097\/01.jcp.0000246216.26400.db","volume":"26","author":"N Acharya","year":"2006","unstructured":"Acharya N, Rosen AS, Polzer JP, et al. 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