Welcome to the CCO Site

Thank you for your interest in CCO content. As a guest, please complete the following information fields. These data help ensure our continued delivery of impactful education. 

Become a member (or login)? Member benefits include accreditation certificates, downloadable slides, and decision support tools.


Bipolar Depression: Current and Future Options

Michael Asbach, DMSc, PA-C, Psych-CAQ

Associate Director
Interventional Psychiatry
DENT Neurologic Institute
Amherst, New York

Michael Asbach, DMSc, PA-C, Psych-CAQ: consultant/advisor/speaker: AbbVie, Avanir, Biogen, Intracellular, Janssen, Neurocrine, Otsuka.

View ClinicalThoughts from this Author

Released: December 23, 2022

Key Takeaways

  • Current standard of care in bipolar depression includes mood stabilizers, second-generation antipsychotics, and—to a lesser extent—antidepressants.
  • Despite existing treatment options, there remains a great need to improve the treatment landscape for bipolar depression.
  • Research is ongoing to identify more effective strategies for bipolar depression treatment, including neurosteroids, psychedelics, and repetitive transcranial magnetic stimulation.

Current State of Bipolar Depression
Bipolar depression presents with significant clinical challenges. Over several decades, a nosological evolution has transpired, with bipolar depression now viewed as a “spectrum” illness ranging from depressive dominant to a more traditional manic-depressive modulating illness. These clinical ambiguities have contributed to uncertainty in diagnosis for many healthcare professionals—as well as therapeutic confusion. Timely diagnosis, therapeutic consensus, and diagnostic agreement are all important areas where the current understanding of bipolar depression falls short.

A diagnosis of bipolar depression often lags 6-8 years after the initial onset of symptoms; in some cases, the lag is up to 13 years. One leading reason for the delay in diagnosis is that unipolar depression and bipolar depressive episodes will clinically present indistinguishably. Furthermore, the depressive phase of bipolar disorder represents the majority of time ill, with patients experiencing depression ranging from 70% to 81% of time ill. This predominance of presentation has led to many initial misdiagnoses: As many as 40% of people initially diagnosed with unipolar depression are later diagnosed with bipolar disorder.

Bipolar depression is associated with high rates of functional impairment and disability, as well as morbidity. Suicide risk is 10-30 times higher for patients with bipolar disorder compared with the general population, with depressive and mixed-mood states carrying the highest risk of suicidal behavior. Delays in accurate diagnosis consequently lead to delays in appropriate treatment, thereby playing a large role in these high rates of functional impairment and morbidity.

Shortcomings in the Current Treatment of Bipolar Depression
Bipolar depression is widely thought to require a different pharmacologic approach than major depressive disorder (MDD), despite its clinical similarities. The majority of bipolar disorder is represented by the depressive phase of illness, but there is concern that the use of antidepressants risks switching the patient into a manic or agitated mood state. Although the absolute risk of antidepressant-induced mood activation is not definitive, the STEP-BD trial found that antidepressant performance was similar to placebo as treatment of bipolar depression.

Alternative treatment options include mood stabilizers such as lithium and second-generation antipsychotics. For more than 50 years, lithium has been one of the most effective treatments for bipolar disorder, often recommended as first-line therapy by many treatment guidelines. Yet, it remains underused given the wealth of empirical evidence supporting its efficacy and safety. In the past decade, second-generation antipsychotics have become a mainstay of bipolar depression treatment, with several agents receiving an FDA indication for bipolar depression in the past few years. Most of these approved agents are associated with a modest treatment effect in bipolar depression. However, they also are associated with adverse events at therapeutic dosing including restlessness, sedation, metabolic disorders, and drug-induced movement disorders.

Looking Ahead: Innovations in Bipolar Depression Therapies
The need to innovate and identify novel therapeutic approaches is felt across the mental health spectrum, and bipolar depression is no exception. Several novel therapies have shown promise in the treatment of bipolar depression. Ketamine is a glutamatergic modulator that has emerged as a rapid and effective intervention of acute MDD. There is growing evidence that ketamine may have clinical utility in bipolar depression, but the studies remain small with varying quality. Some case reports of ketamine-inducing affective switching exist, but more research is needed to assess risk of mood destabilization. Esketamine, an enantiomer of ketamine, is indicated for MDD. There are no placebo-controlled trials involving esketamine for bipolar depression, but a recent case study of intranasal esketamine in a patient with bipolar depression—in addition to promising evidence of the efficacy of racemic ketamine—suggests that further investigation is needed.

Other approaches include neurosteroids and psychedelics. Neurosteroids have been a promising realm of clinical research for MDD, postpartum depression, and insomnia. These GABAA-modulating agents should be investigated further, specifically within bipolar depressive illness. Classic psychedelics such as LSD, psilocybin, mescaline, and ayahuasca stimulate the serotonin 2A receptor and have shown promise in the treatment of unipolar depression, posttraumatic stress disorder, and obsessive-compulsive disorder. Unfortunately, patients with bipolar depression have been excluded from psychedelic research due to case reports of manic and psychotic inducement in vulnerable patients.

Neuromodulation also carries promise as an innovative treatment approach for bipolar depression. Repetitive transcranial magnetic stimulation (rTMS) was cleared by the FDA as a treatment of MDD in 2008. Recently, many small-scale studies have demonstrated both efficacy and safety profiles using rTMS for the treatment of bipolar depression.

Treatment of bipolar depression remains an unmet clinical need. Although more treatments are available, the illness remains debilitating and a leading cause of morbidity among mental health disorders. Several second-generation antipsychotics now are approved for use in bipolar depression, and they have been shown to have moderate effect. Although treatment of bipolar depression is far less investigated than MDD, promising innovations are in the development pipeline.

Your Thoughts?
With so many developments ongoing in treatment of bipolar depression, it can be difficult to stay on top of the most current research. Which strategies and research would you like more information about? Answer the polling question and join the discussion by posting a comment.


  • Bahji A, Zarate CA, Vazquez GH. Ketamine for bipolar depression: a systematic review. Int J Neuropsychopharmacol. 2021;24:535-541.
  • Baldessarini RJ, Vázquez GH, Tondo L. Bipolar depression: a major unsolved challenge. Int J Bipolar Disord. 2020;8:1.
  • Bhatt K, Yoo J, Bridges A. Ketamine-induced manic episode. Prim Care Companion CNS Disord. 2021;23:20l02811.
  • Dean RL, Marquardt T, Hurducas C, et al. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database Syst Rev. 2021;10:CD011611.
  • Dome P, Rihmer Z, Gonda X. Suicide risk in bipolar disorder: a brief review. Medicina (Kaunas). 2019;55:403.
  • Forte A, Baldessarini RJ, Tondo L, et al. Long-term morbidity in bipolar-I, bipolar-II, and unipolar major depressive disorders. J Affect Disord. 2015;178:71-78.
  • Fritz K, Russell AMT, Allwang C, et al. Is a delay in the diagnosis of bipolar disorder inevitable? Bipolar Disord. 2017;19:396-400.
  • Gold AK, Ornelas AC, Cirillo P, et al. Clinical applications of transcranial magnetic stimulation in bipolar disorder. Brain Behav. 2019;9:e01419.
  • Lin Y, Mojtabai R, Goes FS, et al. Trends in prescriptions of lithium and other medications for patients with bipolar disorder in office-based practices in the United States: 1996-2015. J Affect Disord. 2020;276:883-889.
  • Martinez-Botella G, Salituro FG, Harrison BL, et al. Neuroactive steroids: SAGE- 217, a clinical next-generation neuroactive steroid positive allosteric modulator of the GABAA receptor. J Med Chem. 2017;60:7810-7819.
  • Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356:1711-1722.
  • Shen H, Zhang L, Xu C, et al. Analysis of misdiagnosis of bipolar disorder in an outpatient setting. Shanghai Arch Psychiatry. 2018;30:93-101.
  • Skriptshak C, Reich A. Intranasal esketamine use in bipolar disorder: a case report. Ment Health Clin. 2021;11:259-262.
  • Tondo L, Visioli C, Preti A, et al. Bipolar disorders following initial depression: modeling predictive clinical factors. J Affect Disord. 2014;167:44-49.

Leaving the CCO site

You are now leaving the CCO site. The new destination site may have different terms of use and privacy policy.


Cookie Settings