Treatment Strategies for Bipolar Depression

Charles L. Bowden, MD

Department of Psychiatry, University of Texas Health Science Center, and the Center for Bipolar Illness Interventions in Hispanic Communities, San Antonio


Phases of Bipolar Treatment

The basic strategy and time course for treating bipolar disorder has shifted in recent years. Successful treatment of bipolar disorder can generally be divided into 3 phases: acute assessment and stabilization, continuation therapy, and maintenance therapy (AV 1AV 1).1

To provide syndromal recovery in the acute phase, clinicians should maximize mood stabilizer treatment and add adjunctive treatments as needed. Clinicians should provide support, a structured treatment plan, and education about lifestyle changes, habits, and avoidance of certain destabilizing factors. Clinicians should also involve the family in the treatment process.

Continuation therapy for bipolar disorder begins after syndromal recovery and is meant to achieve and sustain functional recovery. Clinicians' general goals during this treatment phase include optimizing medications for tolerability, tapering adjunctive medications whenever possible to simplify the regimen, and introducing psychosocial or psychoeducational therapy. A goal of nonpharmacologic therapy should be to teach patients how to monitor their illness so that they can avoid relapse by recognizing and managing fluctuations in symptomatology that might impair functionality.

Maintenance therapy should maximize long-term stability and function in patients with bipolar depression. Patients should learn to anticipate and recognize bipolar prodromes so that the illness can be managed with longer intervals between clinical checkups. Additionally, clinicians should focus on optimizing adaptation to the disorder so that patients can function as much as possible like people without bipolar disorder.

Continuing Acute Pharmacotherapy in the Maintenance Phase

One strategy for maintenance treatment of bipolar disorder is to continue the same treatment that stabilized the patient during the acute phase. Unfortunately, a dearth of information exists regarding the specifics involved in moving from acute therapy into the continuation and maintenance phases of bipolar treatment. The question of whether the drug regimen that resolved the acute episode remains effective in maintenance treatment has not been extensively studied.


Maintenance Therapy After Depressive Episodes

In a study2 of recently depressed patients with bipolar I disorder who were stabilized with lamotrigine monotherapy or lamotrigine in combination with any other psychotropic agent, maintenance treatment with lamotrigine or lithium was observed for 18 months. Before the double-blind maintenance treatment began, all agents except lamotrigine (including lithium) were discontinued. Compared with placebo, lamotrigine was significantly superior at delaying depressive relapse (P = .047), and lithium was significantly superior at delaying manic relapse (P = .026).

Several atypical antipsychotics are approved for the treatment of acute manic or mixed bipolar episodes, but only quetiapine and the olanzapine-fluoxetine combination are indicated for bipolar depression. The BipOLar DEpRession (BOLDER)3,4 studies found quetiapine to be effective for bipolar depression at doses of 300 mg/d and 600 mg/d. Olanzapine-fluoxetine was found to have superior depressive symptom improvement compared with lamotrigine in bipolar I disorder, but the combination treatment was associated with more treatment-emergent side effects than lamotrigine.5

Olanzapine and aripiprazole are approved for bipolar maintenance treatment, but, given the limited amount of available evidence, the current best strategy for the use of atypical antipsychotics in the maintenance phase might be to continue using the therapy that was effective for acute treatment.


Antidepressant monotherapy is not recommended for bipolar maintenance in patients who were recently depressed6 (for more information, see
"Role of Antidepressants in Bipolar Depression"). Unfortunately, psychiatrists and general practitioners alike are still prescribing antidepressant monotherapy to many patients with bipolar depression, so these patients fail to receive mood stabilizers, which are a fundamental part of treatment. Even when antidepressants are combined with mood stabilizers, no additional benefit is apparent compared with mood stabilizer monotherapy (AV 2AV 2).7 However, should an acute bipolar depressive episode be treatment-refractory with mood stabilizer monotherapy or should a breakthrough depressive episode occur during maintenance therapy, an antidepressant can be tried. Evidence from a small study8 suggests that, if the patient responds, the combination treatment can be continued with positive results.

Considering Tolerability

When considering an overall treatment strategy and choosing among drugs that might not have clear differences in efficacy, tolerability may be a deciding factor. For instance, both lamotrigine and divalproex are associated with significantly fewer study dropouts due to adverse events compared with lithium.9

A large maintenance study10 that compared subjects initially in a mixed manic state to those initially in a nonmixed or euphoric manic state found that subjects in mixed manic states discontinued treatment because of adverse events at twice the rate of subjects with euphoric mania regardless of which medication was being used. Thus, for mixed mania, or possibly bipolar depression, the fundamental psychopathology of the mood episode may predispose patients to increased intolerability regardless of the medication.

For Clinical Use

  • After stabilizing an acute episode, institute adjunctive psychoeducation to help prevent relapse
  • Consider alternatives to lithium monotherapy as it appears to have a weak relationship between acute and maintenance efficacy
  • Do not prescribe antidepressants without mood stabilizers to patients with bipolar disorder

Drug Names

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

Take the online posttest.


  1. Sachs GS. Bipolar mood disorder: practical strategies for acute and maintenance phase treatment. J Clin Psychopharmacol. 1996;16(2 suppl 1):32S–47S.
  2. 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.
  3. Calabrese JR, Keck PE Jr, Macfadden W, et al, for the BOLDER Study Group. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162(7):1351–1360.
  4. Thase ME, Macfadden W, Weisler RH, et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (the BOLDER II study). J Clin Psychopharmacol. 2006;26(6):600–609. Correction in 2007;27(1):51.
  5. 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.
  6. Suppes T, Dennehy EB, Hirschfeld RMA, et al. The Texas Implementation of Medication Algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66(7):870–886.
  7. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med. 2007;356(17):1711–1722.
  8. Altshuler LL, Post RM, Hellemann G, et al. Impact of antidepressant continuation after acute positive or partial treatment response for bipolar depression: a blinded, randomized study. J Clin Psychiatry. 2009;70(4):450–457.
  9. Smith LA, Cornelius V, Warnock A, et al. Effectiveness of mood stabilizers and antipsychotics in the maintenance phase of bipolar disorder: a systematic review of randomized controlled trials. Bipolar Disord. 2007;9(4):394–412.
  10. Bowden CL, Collins MA, McElroy SL, et al. Relationship of mania symptomatology to maintenance treatment response with divalproex, lithium, or placebo. Neuropsychopharmacology. 2005;30(10):1932–1939.