Current Psychiatry Reports

, 16:431 | Cite as

Options for Pharmacological Treatment of Refractory Bipolar Depression

  • Leonardo TondoEmail author
  • Gustavo H. Vázquez
  • Ross J. Baldessarini
Bipolar Disorders (WH Coryell, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Bipolar Disorders


Bipolar disorders of types I and II, even when treated by currently standard options, show a marked excess of depressive morbidity. Treated, type I patients in mid-course or from the onset of illness are ill, overall, 50 % of weeks of follow-up, and 75 % of that unresolved morbidity is depressive. Currently widely held impressions are that bipolar depression typically is poorly responsive to antidepressants, that treatment-resistant depression (TRD) is characteristic of the disorder, and that risk of mania with antidepressant treatment is very high. However, none of these views is supported consistently by available research. TRD may be more prevalent in bipolar than unipolar mood disorders. Relatively intense research attention is directed toward characteristics and treatments of TRD in unipolar depression, but studies of bipolar TRD are uncommon. We found only five controlled trials, plus 10 uncontrolled trials, providing data on a total of 13 drug treatments, all of which involved one or two trials, in 87 % as add-ons to complex, uncontrolled regimens. In two controlled trials, ketamine was superior to placebo but it is short-acting and not orally active; pramipexole was weakly superior to placebo in one controlled trial; three other drugs failed to outperform controls. Other pharmacotherapies are inadequately evaluated and nonpharmacological options are virtually untested in bipolar TRD. The available research supports the view that antidepressants may be effective in bipolar depression provided that currently agitated patients are excluded, that risk of mania with antidepressants is only moderately greater than risk of spontaneous mania, and that bipolar TRD is not necessarily resistant to all treatments.


Amphetamine Aripiprazole Bipolar disorder Bupropion Creatine Depression Inositol Ketamine Ketoconazole Lamotrigine Methylphenidate Modafinil N-acetylcysteine Pramipexole Quetiapine Risperidone, Stimulants Treatment resistance Tri-iodothyronine 



Supported by an award from the Aretæus Association of Rome (to L. Tondo), and a grant from the Bruce J. Anderson Foundation and by the McLean Private Donors Research Fund (to R.J. Baldessarini).

Compliance with Ethics Guidelines

Conflict of Interest

Leonardo Tondo, Gustavo H. Vázquez, and Ross J. Baldessarini declare that they have no potential bases of apparent conflict of interest in the material presented here.

Human and Animal Rights and Informed Consent

This article contains observational data from a study by Tondo and Baldessarini (2013) in patients providing informed consent for anonymous and aggregate use of data arising from their treatment (cited in footnote 2). No animal studies were involved.


Recently published papers of particular interest have been highlighted as: • Of importance •• Of major importance

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Leonardo Tondo
    • 1
    • 3
    • 5
    Email author
  • Gustavo H. Vázquez
    • 1
    • 4
  • Ross J. Baldessarini
    • 1
    • 2
  1. 1.International Consortium for Bipolar and Psychotic Disorder ResearchMcLean HospitalBelmontUSA
  2. 2.Department of PsychiatryHarvard Medical SchoolBostonUSA
  3. 3.Lucio Bini Mood Disorder CentersCagliari & RomeItaly
  4. 4.Department of NeurosciencePalermo UniversityBuenos AiresArgentina
  5. 5.Mailman Research CenterMcLean HospitalBelmontUSA

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