CME Feature: Clinical Advances In Bipolar Disorder

Managing Bipolar Depression: Best Practices and Emerging Therapies



APA = American Psychiatric Association; CINP = International College of Neuro-Psychopharmacology; BAP = British Association for Psychopharmacology; Florida Best Practice = 2017-2018 Florida Best Practice Psychotherapeutic Medication Guidelines for Adults; CANMAT = Canadian Network for Mood and Anxiety Treatments; ISBD = International Society for Bipolar Disorders

*As of December 2018, under FDA review as a treatment for depressive episodes associated with bipolar I disorder in adults.


Hierarchy of treatment based on efficacy, safety and tolerability.

Bipolar I disorder
  • 1st line treatments (in order of recommendation)
    • Quetiapine (level 1 evidence)
    • Lurasidone plus lithium or divalproex (level 1 evidence)
    • Lithium (level 2 evidence)
    • Lamotrigine monotherapy (level 2 evidence)
    • Lurasidone monotherapy (level 2 evidence)
    • Adjunctive lamotrigine (level 2 evidence)
  • 2nd line treatments
    • Divalproex (level 2 evidence)
    • Adjunctive SSRI or bupropion (level 1 evidence)
    • ECT (level 4 evidence)
    • Cariprazine (level 1 evidence)
    • Olanzapine/fluoxetine combination (level 2 evidence)
Bipolar II disorder
  • 1st line – quetiapine (level 1 evidence)
  • 2nd line
    • Lithium (level 2 evidence)
    • Lamotrigine (level 2 evidence)
    • Adjunctive bupropion (level 2 evidence)
    • ECT (level 3 evidence)
    • Sertraline (level 2 evidence)
    • Venlafaxine (level 2 evidence)
Florida Best Practice Guideline 2017/2018

Available from:

  • Selection of acute treatment should take maintenance treatment goals into account
  • Level 1 Recommendations (established efficacy)
    • Optimize current mood stabilizer and check blood levels, if appropriate
    • Quetiapine or lurasidone monotherapy
      • Notes: only quetiapine has been established as efficacious for bipolar II, lurasidone has a more favorable metabolic profile
    • Lamotrigine monotherapy
    • Lurasidone or lamotrigine plus lithium or divalproex
      • Note itneraction between lamotrigine and divalproex requiring dose reduction of lamotrigine
    • Antidepressants NOT recommended first-line
  • Level 2A Recommendations (established efficacy, but with safety concerns)
    • Olanzapine/fluoxetine combination for bipolar I disorder
  • Level 2B Recommendations (better tolerability, but limited efficacy)
    • Lithium for bipolar I disorder
    • 2 drug combination of above medications
  • Level 3 (if above are ineffective and/or not well tolerated) – ECT
  • Level 4 (if above are ineffective and/or not well tolerated)
    • Cariprazine
    • Mood stabilizer/antipsychotic plus antidepressant (e.g. SSRI)
      • Note: Antidepressant monotherapy is not recommended in bipolar I depression
      • Note: Superiority of antidepressant monotherapy versus adjunctive mood stabilizer with antidepressant for treatment of bipolar II depression is uncertain.
    • Pramipexole
    • Adjunctive modafinil, thyroid hormone (T3) or stimulant
    • 3 drug combination
    • Transcranial magnetic stimulation (TMS)
CINP 2017 Algorithm

Fountoulakis KN, Yatham L, Grunze H, Vieta E, Young A, Blier P et al. The International College of Neuro-Psychopharmacology (CINP) treatment guidelines for bipolar disorder in adults (CINP-BD-2017), part 2: review, grading of the evidence and a precise algorithm. Int J Neuropsychopharmacol. 2017;20(2):121-179.

  • 1st line – quetiapine or lurasidone
    • Consider CBT adjunctive
  • 2nd line options
    • Add mood stabilizer to lurasidone, modafinil or pramipexole
    • Lithium plus lamotrigine
    • Olanzapine monotherapy or olanzapine/fluoxetine combination
    • For patients with rapid cycling
      • Bipolar I – start with valproate
      • Bipolar II – start with lithium
    • 3rd line – valproate, aripiprazole, imipramine, phenelzine, carbamazepine or lamotrigine monotherapy, or lithium plus L-sulpiride
    • 4th line options
      • Tranylcypromine or lithium monotherapy
      • Venlafaxine preferably in combination with an antimanic medication
      • Armodafinil or ketamine plus a mood stabilizer
      • Lithium plus fluoxetine
      • Mood stabilizer plus levothyroxine
      • Lithium plus oxcarbazepine
    • 5th line – ECT or combination of medications not previously tried
Selected Key Points – BAP 2016

Goodwin GM, Haddad PM, Ferrier IN, Aronson JK, Barnes TRH, Cipriani A, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30(6):495-553.

Treatment of acute depressive episodes:

  • In patients not already taking long-term maintenance treatment for bipolar disorder
    • consider quetiapine, lurasidone or olanzapine (moderate grade recommendation)
    • antidepressants have not been adequately studied, only the combination of fluoxetine with olanzapine is specifically supported by literature (moderate grade recommendation)
    • if antidepressants are used, they should be co-prescribed with a drug with proven efficacy for mania (e.g. atypical antipsychotic, lithium, valproate) if the patient has a history of mania (standard of care)
    • consider initial treatment with lamotrigine, usually together with an agent that would prevent the recurrence of mania (high grade recommendation)
    • consider ECT for patients with high suicidal risk, treatment resistance, psychosis or during pregnancy (moderate grade recommendation)
    • lithium may be considered when depressive symptoms are less severe (low grade recommendation)
    • consider family-focused, cognitive behavior therapy or interpersonal rhythm therapy (low grade evidence)
  • In patients currently taking long-term maintenance treatment for bipolar disorder
    • optimize long-term treatment by checking the dose and/or serum concentration is adequate (standard of care)
    • if the patient fails to respond, initiate treatment as above

Selected Key Points – APA Guideline Watch 2005

Hirschfeld RMA. Guideline watch: practice guideline for the treatment of patients with bipolar disorder, 2nd edition. Available from:

  • Medications with the strongest evidence for acute depression: olanzapine/fluoxetine combination, quetiapine, lamotrigine
  • Adjunctive pramipexole may be effective
  • Antidepressants without a mood stabilizer is not recommended for bipolar I disorder
Selected Key Points – APA Guidelines 2002

Hirschfeld RMA, Bowden CL, Gitlin MJ, Keck PE, Suppes T, Thase ME, et al. Practice guideline for the treatment of patients with bipolar disorder second edition. Available from:

  • Goals of treatment:
    • Achieve remission and return the patient to previous level of functioning
    • Avoid precipitating a manic or hypomanic episode
  • Initial treatment:
    • For patients not yet in treatment, initiate either lithium or lamotrigine
      • Consider lithium plus antidepressant for more severely ill patients
      • Antidepressant monotherapy is not recommended
      • Consider ECT for suicidal patients, psychosis or during pregnancy
      • Interpersonal therapy and cognitive behavioral therapy may be useful adjunctively
    • For patients who suffer a breakthrough depressive episode on maintenance medication
      • Optimize medication dosage
      • Ensure that blood levels are within the therapeutic range
      • If the patient fails to respond to optimized maintenance medication, consider adding lamotrigine, bupropion, or paroxetine
        • Alternatives – add another SSRI, venlafaxine or MAOI
        • TCAs are not recommended due to potentially higher risk of precipitating a switch to mania
        • Consider ECT for treatment-resistant depression, psychosis or catatonic features
        • Antidepressants may be used earlier for bipolar II depression than bipolar I depression due to potentially lower risk of antidepressant-induced switch to mania/hypomania