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 journalReview articlepeer-review

33 Scopus citations


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 (US)
Pages (from-to)S24-S33
JournalJournal of Affective Disorders
Issue numberS1
StatePublished - 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

  • Clinical Psychology
  • Psychiatry and Mental health


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