Balancing benefits and harms of treatments for acute bipolar depression

Terence A. Ketter, Shefali Miller, Bernardo Dell'Osso, Joseph R. Calabrese, Mark A. Frye, Leslie Citrome

Research output: Contribution to journalArticlepeer-review


Background Bipolar depression is more pervasive than mania, but has fewer evidence-based treatments.

Methods Using data from multicenter, randomized, double-blind, placebo-controlled trials and meta-analyses, we assessed the number needed to treat (NNT) for response and the number needed to harm (NNH) for selected side effects for older and newer acute bipolar depression treatments.

Results The 2 older FDA-approved treatments for bipolar depression, olanzapine-fluoxetine combination (OFC) and quetiapine (QTP) monotherapy, were efficacious (response NNT=4 for OFC, NNT=6 for QTP), but similarly likely to yield harms (OFC weight gain NNH=6; QTP sedation/somnolence NNH=5). Commonly used unapproved agents (lamotrigine monotherapy and adjunctive antidepressants) tended to be well-tolerated (with double-digit NNHs), although this advantage was at the cost of inadequate efficacy (response NNT=12 for lamotrigine, NNT=29 for antidepressants). In contrast, the newly approved agent lurasidone was not only efficacious (response NNT=5 for monotherapy, NNT=7 as adjunctive therapy), but also had enhanced tolerability (NNH=15 for akathisia [monotherapy], NNH=16 for nausea [adjunctive]). Although adjunctive armodafinil appeared well tolerated, its efficacy in bipolar depression has not been consistently demonstrated in randomized controlled trials.

Limitations NNT and NNH are categorical metrics; only selected NNHs were assessed; limited generalizability of efficacy (versus effectiveness) studies.

Conclusion For acute bipolar depression, older approved treatments may have utility in high-urgency situations, whereas lamotrigine and antidepressants may have utility in low-urgency situations. Newly approved lurasidone may ultimately prove useful in diverse situations. New drug development needs to focus on not only efficacy but also on tolerability.

Original languageEnglish
Pages (from-to)S24-S33
JournalJournal of Affective Disorders
Issue numberS1
Publication statusPublished - Dec 1 2014


  • Antidepressants
  • Antidepressants
  • Antipsychotics
  • Armodafinil
  • Bipolar depression
  • Bipolar disorder
  • Lamotrigine
  • Lurasidone
  • Mood stabilizers
  • Number needed to harm
  • Number needed to treat
  • Olanzapine plus fluoxetine
  • Quetiapine

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Clinical Psychology
  • Medicine(all)


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