Long-Term Treatment of Bipolar Depression and Other Issues

Eduard Vieta, MD, PhD

Department of Psychiatry and the Bipolar Disorders Program, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain

Bipolar disorder is a highly recurrent illness that usually requires long-term or lifelong treatment to control symptoms and stabilize mood.1 Clinicians should develop a long-term strategy during the acute phase of treatment. The acute phase must be followed by a continuation phase, which typically consists of the same treatment, possibly at a lower dose, and, depending on the agent, an additional medication may be needed for prophylaxis. In some patients, monotherapy is sufficient, but, in most cases, combination therapy is necessary. Because patients spend substantially more time depressed than manic,2,3 bipolar depression relapse should be a major concern during maintenance therapy. However, antidepressant monotherapy is not recommended.1 (For more information on antidepressants in bipolar depression, see "Role of Antidepressants in Bipolar Depression.")

Efficacy of Maintenance Treatment Options

Several agents have demonstrated efficacy as maintenance treatment for bipolar disorder; however, some are supported by stronger evidence than others (ie, at least 1 positive, fully powered, randomized, double-blind, placebo-controlled, parallel-group monotherapy trial). Drugs with this level of support include lithium, lamotrigine, quetiapine, olanzapine, aripiprazole, ziprasidone (as adjunctive therapy), and long-acting injectable risperidone (as adjunctive therapy).

Monotherapy trials. A placebo-controlled trial4 found both lithium and lamotrigine to be significantly superior to placebo in the prevention of any mood episode (AV 1AV 1). Lamotrigine was significantly better than placebo at preventing depressive episodes (P = .047), while lithium was significantly superior to placebo at preventing manic or hypomanic episodes (P = .026).

Quetiapine probably has the most evidence of efficacy for long-term treatment of bipolar depression. Two continuation phase studies5,6 and 1 maintenance phase study7 in patients stabilized with quetiapine found that continuing quetiapine significantly lengthened the time to recurrence of any mood event compared with switching to placebo.

In patients whose manic or mixed episodes had remitted with olanzapine monotherapy, the relapse rate during maintenance treatment with olanzapine was about 47% compared with about 80% with placebo.8 Aripiprazole monotherapy over 100 weeks for patients whose manic or mixed episodes were initially stabilized with aripiprazole was superior to placebo in delaying manic (P = .005) but not depressive (P = .602) relapse.9

Combination therapy trials. Brown et al10 compared the efficacy of the olanzapine-fluoxetine combination with that of lamotrigine in patients with bipolar depression. Onset of action was significantly shorter with olanzapine-fluoxetine than with lamotrigine (P = .010); this was probably related to the titration of lamotrigine that is needed to prevent skin rash. Although the olanzapine-fluoxetine group showed significantly greater improvement on the CGI-S than the lamotrigine group at 7 weeks (P = .002), a 6-month follow-up study11 reported no significant difference between the 2 groups in rates of relapse.

In contrast to the majority of studies, which address only 1 pole of bipolar disorder, usually mania, colleagues and I12 conducted a long-term trial that included patients experiencing any episode of bipolar disorder. After receiving open-label quetiapine combined with lithium or divalproex and achieving stabilization, patients were randomly assigned to double-blind treatment with quetiapine plus lithium or divalproex or placebo plus lithium or divalproex for up to 104 weeks. Irrespective of the index episode, the long-term quetiapine combination therapy significantly prolonged time to recurrence of any mood event compared with either placebo group (AV 2AV 2). Another study13 with the same design also reported that quetiapine combined with a mood stabilizer was more efficacious in preventing any mood event than placebo plus a mood stabilizer.

Two recent studies14,15 support the maintenance adjunctive use of ziprasidone and long-acting injectable risperidone. However, these trials basically enrolled patients experiencing an acute manic episode and were only powered to show benefits in the prevention of any mood episode, not mania and depression separately.

Psychotherapy trials. Medication alone does not sufficiently protect against recurrence; psychological therapy is also needed.1 Psychoeducation may be the best approach for patients with bipolar depression. In fact, a 2-year study16 reported that patients who received both medication and psychoeducation had significantly fewer total recurrences and depressive episodes compared with those who received pharmacologic monotherapy (AV 3AV 3). Further, in a 5-year study,17 patients who were treated with adjunctive group psychoeducation had more time between recurrences, had fewer recurrences of all mood episodes, and spent less time acutely ill than patients who participated in a nonstructured group intervention.

Other therapies. Maintenance ECT18 or VNS19 may be used in chronically depressed, treatment-resistant, and frequently relapsing patients with bipolar disorder.


For Clinical Use

  • Develop a long-term strategy during acute treatment of bipolar depression
  • Use medications that have evidence of efficacy in both the short- and long-term treatment of bipolar depression, such as lithium, lamotrigine, and quetiapine
  • Supplement pharmacologic treatment with psychoeducation

Drug Names

aripiprazole (Abilify), divalproex (Depakote and others), lamotrigine (Lamictal and others), lithium (Lithobid, Eskalith, and others), olanzapine (Zyprexa), olanzapine-fluoxetine (Symbyax), quetiapine (Seroquel), risperidone (Risperdal Consta), ziprasidone (Geodon)


CGI-S=Clinical Global Impressions-Severity of Illness scale
ECT=electroconvulsive therapy
VNS=vagus nerve stimulation

Take the online posttest.


  1. Vieta E. Maintenance therapy for bipolar disorder: current and future management options. Expert Rev Neurother. 2004;4(6 suppl 2):S35–S42.
  2. Judd LL, Akiskal HS, Schettler PJ, et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6):530–537.
  3. Judd LL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry. 2003;60(3):261–269.
  4. Calabrese JR, Bowden CL, Sachs G, et al, for the Lamictal 605 Study Group. A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. J Clin Psychiatry. 2003;64(9):1013–1024.
  5. Young A, McElroy S, Chang W, et al. Placebo-controlled study with acute and continuation phase of quetiapine in adults with bipolar depression (EMBOLDEN I) [poster]. Euro Neuropsychopharmacol 2008;18(suppl 4):S371.
  6. Young A, McElroy S, Chang W, et al. Placebo-controlled study with acute and continuation phase of quetiapine in adults with bipolar depression (EMBOLDEN II) [poster]. Euro Neuropsychopharmacol 2008;18(suppl 4):S371.
  7. Nolen WA, Weisler RH, Neijber A, et al. Quetiapine or lithium versus placebo for maintenance treatment of bipolar I disorder after stabilization on quetiapine [poster]. Presented at the 17th European Congress of Psychiatry; January 24–28, 2009; Lisbon, Portugal.
  8. Tohen M, Calabrese JR, Sachs GS, et al. Randomized, placebo-controlled trial of olanzapine as maintenance therapy in patients with bipolar I disorder responding to acute treatment with olanzapine. Am J Psychiatry. 2006;163(2):247–256.
  9. Keck PE Jr, Calabrese JR, McIntyre RS, et al. Aripiprazole monotherapy for maintenance therapy in bipolar I disorder: a 100-week, double-blind study versus placebo. J Clin Psychiatry. 2007;68(10):1480–1491.
  10. Brown EB, McElroy SL, Keck PE Jr, et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry. 2006;67(7):1025–1033.
  11. Brown E, Dunner DL, McElroy SL, et al. Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I depression [published online ahead of print December 11, 2008]. Int J Neuropsychopharmacol. doi: 10.1017/S1461145708009735.
  12. Vieta E, Suppes T, Eggens I, et al. Efficacy and safety of quetiapine in combination with lithium or divalproex for maintenance of patients with bipolar I disorder (international trial 126). J Affect Disord. 2008;109(3):251–263.
  13. Suppes T, Vieta E, Liu S, et al. Maintenance treatment for patients with bipolar I disorder: results from a North American study of quetiapine in combination with lithium or divalproex (trial 127). Am J Psychiatry. 2009;166(4):476–488.
  14. Vieta E, Bowden C, Ice K, et al. A 6-month, randomized, placebo-controlled, double blind trial of ziprasidone plus a mood stabilizer in subjects with bipolar I disorder [poster]. Eur Psychiatry. 2009;24(suppl 1):S594.
  15. Alphs L, Kujawa M, Macfadden W, et al. Frequently relapsing bipolar disorder: evidence for an effective treatment using adjunctive risperidone long-acting injectable. Presented at the 14th Biennial Winter Workshop on Schizophrenia and Bipolar Disorders; February 2–7, 2008; Montreux, Switzerland.
  16. Colom F, Vieta E, Reinares M, et al. Psychoeducation efficacy in bipolar disorders: beyond compliance enhancement. J Clin Psychiatry. 2003;64(9):1101–1105.
  17. Colom F, Vieta E, Sánchez-Moreno J, et al. Group psychoeducation for stabilized bipolar disorders: 5-year outcome of a randomised clinical trial. Br J Psychiatry. 2009;194(3):260–265.
  18. Vaidya NA, Mahableshwarkar AR, Shahid R. Continuation and maintenance ECT in treatment-resistant bipolar disorder. J ECT. 2003;19(1):10–6.
  19. Daban C, Martinez-Aran A, Cruz N, et al. Safety and efficacy of vagus nerve stimulation in treatment-resistant depression: a systematic review. J Affect Disorder. 2008;110(1–2):1–15.