CoChat
Sign Up
Cited by 128Bipolar Disorder and TreatmentTreatment of Major DepressionSchizophrenia research and treatment

Treatments for Acute Bipolar Depression: Meta-analyses of Placebo-controlled, Monotherapy Trials of Anticonvulsants, Lithium and Antipsychotics

Open access
Selle, V., Schalkwijk, S., Vázquez, G., Baldessarini, R.·2014·Pharmacopsychiatry
DOI 10.1055/s-0033-1363258
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Optimal treatments for bipolar depression, and the relative value of specific drugs for that purpose, remain uncertain, including agents other than antidepressants. METHODS: We searched for reports of placebo-controlled, monotherapy trials of mood-stabilizing anticonvulsants, second-generation antipsychotics, or lithium for acute major depressive episodes in patients diagnosed with type I or II bipolar disorder and applied random-effects meta-analysis to evaluate their efficacy, comparing outcomes based on standardized mean drug-placebo differences (SMD) in improvement, relative response rates (RR), and number-needed-to-treat (NNT). RESULTS: We identified 24 trials of 10 treatments (lasting 7.5 weeks, with ≥ 50 collaborating sites/trial) that met eligibility criteria: lamotrigine (5 trials), quetiapine (5), valproate (4), 2 each for aripiprazole, olanzapine, ziprasidone, and 1 each for carbamazepine, lithium, lurasidone, and olanzapine-fluoxetine. Overall, pooled drug-over-placebo responder-rate superiority (RR) was moderate (29% [CI: 19-40%]), and NNT was 8.2 (CI: 6.4-11). By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥ valproate > quetiapine > lurasidone > olanzapine, aripiprazole, and carbamazepine; ziprasidone was ineffective, and lithium remains inadequately studied. Notably, drugs were superior to placebo in only 11/24 trials (5/5 with quetiapine, 2/4 with valproate), and only lamotrigine, quetiapine and valproate had > 2 trials. Treatment-associated mania-like reactions were uncommon (drugs: 3.7%; placebo: 4.7%). DISCUSSION: Controlled trials of non-antidepressant treatments for bipolar depression remain scarce, but findings with olanzapine-fluoxetine, lurasidone, quetiapine, and perhaps carbamazepine and valproate were encouraging; lithium requires adequate testing.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1055/s-0033-1363258

Cites

66 of 66 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Quetiapine, lithium, lamotrigine, and lurasidone have evidence for efficacy as monotherapy for acute bipolar depression.

    “Quetiapine (level 1),241, 242, 243 lithium (level 2),244, 245, 246 lamotrigine (level 2)242, 247, 248 and lurasidone (level 2)249 are all recommended as first‐line treatment options with evidence for efficacy as monotherapy.”

    From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [242]

    The Meta-analyses section reports favorable efficacy results for quetiapine and lurasidone in placebo-controlled monotherapy trials, although lurasidone had only one trial. It reports that lithium was not superior to placebo and that lamotrigine failed to differ significantly from placebo in four of five trials. The source therefore does not support efficacy for all four drugs. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Ziprasidone monotherapy or adjunctive therapy, lamotrigine in combination with folic acid, and mifepristone adjunctive therapy have evidence for lack of antidepressant efficacy in bipolar depression.

    “Ziprasidone monotherapy or adjunctive therapy (level 1 negative),242, 294 lamotrigine in combination with folic acid (level 2 negative),251 and mifepristone (adjunctive) (Leve 2 negative)295 are also not recommended due to evidence for lack of antidepressant efficacy (Table 15).”

    From Canadian Network for Mood and Anxiety Treatments ( <scp>CANMAT</scp> ) and International Society for Bipolar Disorders ( <scp>ISBD</scp> ) 2018 guidelines for the management of patients with bipolar disorder (2018) · cites this paper as [242]

    The Meta-analyses section reports that ziprasidone was not superior to placebo on any of three outcome measures, supporting the claim about monotherapy in acute bipolar depression. This paper analyzes monotherapy trials, not adjunctive ziprasidone; the folic-acid and mifepristone claims carry separate citations in the citing sentence and are not established by this source. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 12

  1. [5]5. Selle V et al. Treatments for Acute Bipolar … Pharmacopsychiatry 2014; 47: 43-52
  2. [7]7. Samalin L , Llorca P M . Methodological approach to inter "guide- line" variability in the management of bipolar disorders (French) . Encephale 2012 ; 38 : 126 -132
  3. [9]9. Cruz N , Sanchez-Moreno J H , Torres F et al. Effi cacy of modern antip- sychotics in placebo-controlled trials in bipolar depression: meta- analysis . Int J Neuropsychopharmacol 2010 ; 13 : 5 -14
  4. [22]22. Thase M E , Macfadden W , Weisler R H . Effi cacy of quietapine mono- therapy in bipolar I and II depression: double-blind, placebo-control- led (BOLDER II) study . J Clin Psychopharmacol 2006 ; 26 : 600 -609
  5. [27]27. Suppes T , Datto C , Minkwitz M et al. Eff ectiveness of the extended release formulation of quetiapine monotherapy for the treatment of acute bipolar depression . J Aff ect Disord 2010 ; 121 : 106 -115
  6. [31]31. Tohen M , McDonnell D P , Case M et al. Randomized, double-blind, pla- cebo-controlled study of olanzapine in patients with bipolar I depres- sion . Br J Psychiatry 2012 ; 201 : 376 -382
  7. [35]35. Goldsmith D R , Wagstaff A J , Ibbotson T et al. Lamotrigine: review of its use in bipolar disorder . Drugs 2003 ; 63 : 2029 -2050
  8. [38]38. Bond D J , Lam R W , Yatham L N . Divalproex sodium vs. placebo in the treatment of acute bipolar depression: systematic review and meta- analysis . J Aff ect Disord 2010 ; 124 : 228 -234
  9. [40]40. Brown E B , McElroy S L , Keck P E Jr et al. Seven-week, randomized, dou- ble-blind trial of olanzapine/fl uoxetine combination vs. lamotrigine in the treatment of bipolar-I depression . J Clin Psychiatry 2006 ; 67 : 1025 -1033
  10. [42]42. Van der Loos M L , Mulder P G , Hartong E G et al. Effi cacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: multicenter, double-blind, placebo-controlled trial . J Clin Psychiatry 2009 ; 70 : 223 -231
  11. [53]53. Post R M , Uhde T W , Roy-Byrne P P et al. Antidepressant eff ects of car- bamazepine . Am J Psychiatry 1986 ; 143 : 29 -34
  12. [55]55. Saricicek A , Maloney K , Muralidharan A et al. Levetiracetam in man- agement of bipolar depression: randomized, double-blind, placebo- controlled trial . J Clin Psychiatry 2011 ; 72 : 744 -750

Cited by

Sorted by citations

Related

Authors
Selle, V., Schalkwijk, S., Vázquez, G., & Baldessarini, R.
Affiliations
  • McLean Hospital (US)
  • Utrecht University (NL)
  • Harvard University (US)
Corresponding author
Baldessarini, R.
ORCID
Venue
Pharmacopsychiatry
Publisher
Georg Thieme Verlag KG
Published
2014-02-18
Volume
47
Issue
02
Pages
43-52
ISSN
  • 0176-3679 (ISSN-L)
  • 1439-0795
DOI
10.1055/s-0033-1363258
OpenAlex
W2169192603
Cited by
128
References
66
Citations by year
2026: 3 · 2025: 7 · 2024: 6 · 2023: 12 · 2022: 14 · 2021: 11 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 16 · 2016: 8 · 2015: 19 · 2014: 12
FWCI
2.52
Type
journal article
Language
en
Open access
Locations
  • Pharmacopsychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Radboud Repository (Radboud University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Keywords
bipolar depression, bipolar disorder, antiepileptic drugs, lithium, atypical antipsychotics, lamotrigine, quetiapine, valproic acid, lurasidone, carbamazepine, mood stabilizers, monotherapy, treatment efficacy
MeSH terms
Anticonvulsants, Bipolar Disorder, Clinical Trials as Topic, Humans, Antipsychotic Agents, Databases, Factual, Lithium Chloride

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review