Pharmacologic Options for Bipolar Depression

Key Takeaways

• Patients with bipolar disorder spend a significant amount of symptomatic time in a depressive state, but the majority of medication approvals focus on manic or mixed symptoms.
• Currently, only 5 pharmacologic agents are approved for the depressive symptoms of bipolar disorder.
• Trial and failure of at least 2 first-line agents is encouraged in most patients before moving to second-line options or combination therapy.

Bipolar disorder is a serious mental illness that presents healthcare professionals (HCPs) with many unique challenges. Occurring in roughly 3% of the US population, it frequently presents with depressive symptoms, resulting in an initial misdiagnosis for most patients.¹ Although depression accounts for nearly 70% of the symptomatic time in patients with bipolar I and more than 80% in bipolar II, the vast majority of FDA-approved treatments are for acute mania and/or mixed episodes.² Only 5 options are approved for the full spectrum of bipolar disorder. With so few medications carrying approvals for bipolar depression, it is easy to forget that these symptoms are the greatest cause of disability in patients with bipolar disorder.³ As such, it is important for HCPs to know what pharmacologic options—both on and off label—are available and how best to use them. 

Mood Stabilizers
Long hailed as the standard of pharmacologic intervention in bipolar disorder, traditional mood stabilizers are still considered by many to be the workhorses of treatment. Despite their fundamental role, many HCPs are surprised to learn that mood stabilizers lack strong evidence for managing acute depressive episodes. In fact, it may be more accurate to say that the utility of these medications in treating bipolar depression lies in their capacity to maintain stability, thus preventing future episodes, rather than shifting patients out of depression.

In many ways, lithium serves as the classic example of this. Although it is considered first-line therapy by some guidelines, this recommendation seems to stem largely from its well-established benefits as an antimanic and maintenance treatment option in bipolar, as well as its suicide reduction properties. Overall, its efficacy in acute depressive episodes remains largely unproven. In addition, renal elimination and the ongoing need for laboratory monitoring with lithium may limit use in some patients.

Antiepileptics, such as valproic acid and carbamazepine, have shown benefit in several studies, but tolerability concerns and increased teratogenic risks limit widespread utility. Both medications remain unapproved for depressive episodes or ongoing maintenance in bipolar disorder. In addition, carbamazepine carries a high probability for drug interactions through enzyme induction, including increasing its own metabolism. Lamotrigine, while also lacking in strong evidence for depressive symptoms, is supported with data as maintenance drug therapy in bipolar disorder. It is also relatively safe to use and very well tolerated when compared with other antiepileptics. However, the risk of Stevens-Johnson syndrome with lamotrigine requires a slow 5-week titration/retitration schedule, making adherence particularly important. 

Antipsychotics
Currently, second-generation antipsychotics (SGAs), either alone or in combination, are the only medications to have FDA approvals within the spectrum of bipolar depression. Depending on the individual agents, SGAs are uniquely situated as having established both antimanic and antidepressant properties. These effects are likely due to a mixture of dopamine blockade and serotonergic properties (ie, serotonin 2a, 2c, or 7 antagonism, or serotonin 1a receptor partial agonism) of the medications. Receptor binding varies greatly with individual agents, but achieving the proper balance between dopaminergic and serotonergic characteristics appears to be integral in managing bipolar depression. For most, lower doses seem to favor overall serotonergic activity, making them very effective for treating depression. At higher doses, however, dopamine antagonism appears to be the dominant effect, leaving them better suited for managing acute mania. For SGAs with a variable dose range, low to moderate doses likely represent the desired “Goldilocks” balance of activity in bipolar depression. At present, the 5 medications approved to treat the spectrum of bipolar depression include monotherapy with quetiapine, olanzapine + fluoxetine combination (OFC), lurasidone, cariprazine, and lumateperone. In addition, lurasidone and lumateperone are approved for use as adjunctive treatments with mood stabilizers.

When evaluating these options more closely, quetiapine may have one of the most consistent bodies of evidence supporting its use as either monotherapy or off-label adjunctive therapy in bipolar depression. However, the sedating nature of the medication, as well as risks for negative effects on metabolic parameters, warrant consideration. Olanzapine alone has shown benefit in the off-label management of bipolar depression, yet when paired with the selective serotonin reuptake inhibitor (SSRI) fluoxetine, its effects are even more robust. Once again, the significant risks for adverse metabolic outcomes greatly limit use of the medication. Of note, a newer combination product of olanzapine + samidorphan has demonstrated some mitigation of these effects (mostly related to weight gain), but it remains untested in managing bipolar depression. Newer SGAs—such as lurasidone, cariprazine, and lumateperone—are much more metabolically neutral while still demonstrating significant benefits in managing depressive symptoms. Of the three, lurasidone was the first to receive approval and currently has the most published evidence. Nonetheless, cariprazine and lumateperone continue to show promise, as more controlled trials are ongoing.⁴

Antidepressants
The body of evidence describing the off-label use of antidepressants to treat patients with bipolar depression is controversial to say the least. Current evidence does not support the use of any antidepressant as monotherapy due to the risks of inducing mania, mixed features, or rapid cycling.⁵ Only when monotherapy treatments with mood stabilizers and/or SGAs fail should adjunctive treatment with antidepressant be considered, and then only on an individual basis. Traditionally, this involves utilization of SSRIs, serotonin–norepinephrine reuptake inhibitors, or bupropion with an established mood stabilizer or SGA. However, with the exception of OFC, the short-term benefits of this strategy are contentious, and long-term safety has not been established.

Other Treatments
Many other strategies have been considered for off-label use in the treatment of bipolar depression. A comprehensive discussion of these agents is outside the scope of this paper, but some of the most common include other SGAs (ie, aripiprazole, ziprasidone), modafinil, armodafinil, pramipexole, N-acetylcysteine, and ketamine. These treatments are largely considered third-line agents by most evidence-based guidelines due to the lower quality of evidence. Much like the antidepressants, use of any of these treatments should be considered only in individual patients and only after failure of mood stabilizers and/or SGAs. 

Guidelines and Maintenance^6-9
Initial monotherapy options for treatment of acute depressive episodes in bipolar disorder supported by at least 2 major treatment guidelines include quetiapine, lithium, lamotrigine, olanzapine, OFC, and lurasidone. Alternative agents, listed as second-line treatments on at least 2 guidelines and/or first-line agents on only 1 guideline, include valproic acid, carbamazepine, mood stabilizer + SGA, and mood stabilizer or SGA + antidepressant. However, trial and failure of at least 2 first-line agents is encouraged in most patients before moving to second-line options or combination therapy. 

Of note, quetiapine and lamotrigine are the only first-line treatment options included in all 4 guidelines, with lithium and olanzapine (either alone or OFC) being included in 3 guidelines. In addition, the newer SGAs cariprazine and lumateperone received approvals in bipolar depression after the most recent guideline publications. It will be interesting to see their inclusion in future guideline updates considering the prominence of SGAs as a whole in the management of bipolar disorder. 

Maintenance may initially involve ongoing use of acute medications, but the least number of agents at a minimally effective dose is recommended. Monotherapy is considered ideal when possible. This approach lowers adverse event burden, lowers cost, and likely increases compliance.

Your Thoughts?
Options for managing bipolar depression (vs mania) are important to be aware of, as most patients with bipolar disorder spend a majority of symptomatic time in a depressive state. What approach do you take to managing bipolar depression in your practice? Answer the polling question and elaborate in the comments. 

References

1. Hirschfeld RM, Lewis L, Vornik LA. Perceptions and impact of bipolar disorder: how far have we really come? Results of the national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 2003;64:161-174.
2. Baldessarini RJ, Vasquez GH, Tondo L. Bipolar depression: a major unsolved challenge. Int J Bipolar Disord. 2020; 8:1.
3. Sylvia LG, Montana RE, Deckersbach T, et al. Poor quality of life and functioning in bipolar disorder. Int J Bipolar Disord. 2017;5:10.
4. National Institutes of Health US National Library of Medicine. gov. Accessed November 14, 2022.
5. Fornaro M, Anastasia A, Novello S, et al. Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2018;20:195-227.
6. Grunze H, Vieta E, Goodwin GM, et al. The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of bipolar disorders: acute and long-term treatment of mixed states in bipolar disorder. World J Biol Psychiatry. 2017;19:2-58.
7. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20:97-170.
8. National Institute for Health and Care Excellence. Clinical Guideline CG185. Bipolar disorder: assessment and management. nice.org.uk/guidance/cg185. Accessed November 14, 2022
9. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30:495-553.