title: Balancing benefits and harms of treatments for acute bipolar depression.
abstract: 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.
  
  
  CONCLUSIONS
  NNT and NNH are categorical metrics; only selected NNHs were assessed; limited generalizability of efficacy (versus effectiveness) studies.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA. Electronic address: tketter@stanford.edu.
authors.forename: Terence A
authors.initials: TA
authors.lastname: Ketter
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; Sierra Pacific Mental Illness Research Education and Clinical Centers, Palo Alto VA Health Care System, Palo Alto, CA, USA.
authors.forename: Shefali
authors.initials: S
authors.lastname: Miller
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; Department of Psychiatry, University of Milan, Fondazione IRCCS Cà Granda, Milan, Italy.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Dell'Osso
authors.affiliation: Department of Psychiatry, Case Western Reserve, Cleveland, OH, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Calabrese
authors.affiliation: Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Frye
authors.affiliation: Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA.
authors.forename: Leslie
authors.initials: L
authors.lastname: Citrome
mesh_terms: D000208:Acute Disease; D000928:Antidepressive Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D014150:Antipsychotic Agents / Q000008:administration & dosage* / Q000009:adverse effects*; D001569:Benzodiazepines / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy*; D003987:Dibenzothiazepines / Q000627:therapeutic use; D004338:Drug Combinations; D005473:Fluoxetine / Q000627:therapeutic use; D006801:Humans; D054833:Isoindoles / Q000008:administration & dosage / Q000009:adverse effects; D000077213:Lamotrigine; D000069056:Lurasidone Hydrochloride; D015337:Multicenter Studies as Topic; D000069348:Quetiapine Fumarate; D016032:Randomized Controlled Trials as Topic; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects; D014227:Triazines / Q000627:therapeutic use; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D004338:Drug Combinations; D054833:Isoindoles; D013844:Thiazoles; D014227:Triazines; C492572:olanzapine-fluoxetine combination; D005473:Fluoxetine; D001569:Benzodiazepines; D000069348:Quetiapine Fumarate; D000069056:Lurasidone Hydrochloride; D000077213:Lamotrigine
keywords: Antidepressants; Antipsychotics; Armodafinil; Bipolar depression; Bipolar disorder; Lamotrigine; Lurasidone; Mood stabilizers; Number needed to harm; Number needed to treat; Olanzapine plus fluoxetine; Quetiapine