Hayes et al12 conducted one of the most recent large studies to compare lithium with newer second-generation antipsychotics as maintenance monotherapy for bipolar disorder. The authors concluded that for monotherapy, lithium remains the best option. The time to failure (defined as the need to add a second drug to treat symptoms or the need to stop treatment) was approximately twice as long with lithium. This study adds to evidence for the use of lithium as a first-line drug, with antipsychotics as second-line or adjunct therapies.

Continue Reading

Click to enlarge

Post4 reviewed the recommendations in recent clinical trials for first-, second-, and third-line options in treating bipolar disorder. The recommended first-choice therapy is continuation of the medication(s) used to treat the acute episode. For second-line options, data show that lithium once again is the superior initial monotherapy. Data also support valproate, quetiapine, and lamotrigine as second-line options for monotherapy, especially for patients who fail or have contraindications to lithium therapy. Third-line options include drug combinations of lithium or valproate with an antipsychotic.

Long-acting injectable medications

A major problem in the treatment of bipolar disorder is patient noncompliance with treatment. Patients may be given short-term intramuscular antipsychotic treatment for acute mania, but the use of LAI antipsychotics in psychiatry has been increasing during the last decade. Presently, several LAI antipsychotics are available (Table 7). Although several LAI antipsychotics are used for psychosis and schizophrenia, their use for bipolar disorder is off label. Presently, only Risperdal® Consta®, the LAI form of risperidone, has an FDA-approved indication for the treatment of bipolar disorder.13

Click to enlarge

Future research considerations

In their review, Severus et al14 do not make additional treatment recommendations but argue for the necessity of further clinical trials. The authors state that trials should enroll broader populations of patients with bipolar disorder (including patients distinguished by subtype and polarity). Ideally, these patients would be naïve to the treatments used in comparisons. The trials should also more frequently involve direct comparisons between medications. The high relapse rates among patients with bipolar disorder suggest that all current medications are less than ideal. Conducting further clinical trials of current medications, as described, would be beneficial, as well as continuing the development of newer treatments.


The treatment of patients with bipolar disorder requires careful monitoring, conducted best with continuation of care by a primary provider skilled in treatment or by referral to a specialist. For the treatment of acute mania, haloperidol, risperidone, and olanzapine show the best efficacy. If the manic patient has a previous diagnosis of bipolar disorder, his or her prior medication should be continued or restarted if needed. For patients who have bipolar disorder presenting with a depressive episode, antidepressant monotherapy should be avoided. Mixed therapy with fluoxetine and olanzapine or another selective serotonin reuptake inhibitor with quetiapine is recommended. For the maintenance treatment of bipolar disorder, the first-line treatment should be continuation of the medications used during the manic or depressive episode.

Click to enlarge

In case of treatment failure, lithium is the best first-line monotherapy, with valproate, quetiapine (for patients with depression-dominant polarity), and olanzapine (for patients with mania-dominant polarity) as viable alternatives. Second-line dual therapy for patients with resistant symptoms should consist of either lithium or valproate with a second-generation antipsychotic. LAI risperidone is available as an option for noncompliant patients. Patients with bipolar disorder continue to have high relapse rates, indicating that further clinical trials are needed to identify the best options for specific subtypes of patients, and that research into new treatment solutions should be continued.

Ian Ward, PA-C, is an assistant professor of clinical medicine in the Methodist University Physician Assistant Program in Fayetteville, NC


  1. Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381:1672-1682.
  2. Miura T, Noma H, Furukawa TA, et al. Comparative efficacy and tolerability of pharmacological treatments in the maintenance treatment of bipolar disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2014;1:351-359.
  3. Angst F, Stassen HH, Clayton PJ, Angst J. Mortality of patients with mood disorders: follow-up over 34-38 years. J Affect Disord. 2002;68:167-181. 
  4. Post RM. Bipolar disorder in adults: choosing maintenance treatment. UpToDate. http://www.uptodate.com/contents/bipolar-disorder-in-adults-choosing-maintenance-treatment. Updated August 29, 2016. Accessed February 6, 2017.
  5. Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. Lancet. 2011;378:1306-1315.
  6. Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. Neuropsychopharmacology. 2011;36:375-389.
  7. Stovall J. Bipolar disorder in adults: pharmacotherapy for acute mania and hypomania. UpToDate. http://www.uptodate.com/contents/bipolar-disorder-in-adults-pharmacotherapy-for-acute-mania-and-hypomania. Updated May 17, 2016. Accessed February 6, 2017.
  8. Bobo WV, Shelton RC. Bipolar disorder in adults: treating major depression with antidepressants. UpToDate. http://www.uptodate.com/contents/bipolar-disorder-in-adults-treating-major-depression-with-antidepressants. Updated July 13, 2016. Accessed February 6, 2017.
  9. National Institute for Health and Care Excellence (NICE). Bipolar disorder: assessment and management. Clinical guideline (CG185). http://www.nice.org.uk/guidance/cg185. Updated February 2016. Accessed February 6, 2017.
  10. Manning JS. Measuring patient outcomes and making the transition from acute to maintenance treatment for bipolar depression. J Clin Psychiatry. 2015;76:e1603.
  11. Frye MA, Prieto ML, Bobo WV, et al. Current landscape, unmet needs, and future directions for treatment of bipolar depression. J Affect Disord. 2014;169(suppl 1):S17-S23.
  12. Hayes JF, Marston L, Walters K, Geddes JR, King M,Osborn, DP. Lithium vs valproate vs olanzapine vs quetiapine as maintenance monotherapy for bipolar disorder: a population-based UK cohort study using electronic health records. World Psychiatry. 2016;15:53-58.
  13. Chou Y H, Chu P-C, Wu S-W, et al. A systemic review and experts’ consensus for long-acting injectable antipsychotics in bipolar disorder. Clin Psychopharmacol Neurosci. 2015;13:121-128.
  14. Severus E, Schaaff N, Möller H-J. State of the art: treatment of bipolar disorders. CNS Neurosci Ther. 2012;18:214-218.
  15. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Publishing; 2013.