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Day # 51: Bipolar Depression

Welcome back to our current theme of bipolar disorder. In previous lessons we have discussed the clinical manifestations of mania and unipolar depression. Today we are going to focus in on bipolar depression as it has important treatment differences as compared to unipolar depression. Let's jump right in.

Today's Content Level: Intermediate


•As we discussed during the first post of this theme the term "bipolar" means two poles or extremes. The two extreme poles of mood are:

  • Mania (elevated/expansive mood).

  • Depression (low mood).

•Today we are going to discuss bipolar depression. Remember that the defining clinical presentation of bipolar disorder is a manic episode, however depressive episodes are often the biggest contributor towards the morbidity of this disorder. The first mood episode is usually major depression and patients typically have more and longer depressive episodes than episodes of mania/hypomania.

•The clinical criteria of these depressive episodes are similar to that seen in MDD (hint: SIG-E-CAPS), however the illness itself is distinct from unipolar depression and may vary in severity, time course, recurrence, and responds differently to medications.

No traditional antidepressants (SSRIs, SNRIs, TCAs, MAOIs, etc) have shown convincing evidence or received FDA approval for bipolar depression. In fact, the FDA separately approves medications for unipolar vs bipolar depression. Traditional antidepressants used to be prescribed in combination with a mood stabilizer, but this approach has fallen out of favor.

•All currently FDA approved bipolar antidepressants are second-generation antipsychotics with the exception of the fluoxetine + olanzapine combination. In general the evidence based is more limited for bipolar depression, so there is greater controversy in its treatment.


FDA-Approved Medications

  • Olanzapine + Fluoxetine Combination (OFC): Combination shown to be the most effective agent for bipolar depression in a network meta-analysis of 29 randomly controlled trials. Recommended as first-line treatment by the NICE guidelines. Reasonable evidence of prophylactic effect as well. Olanzapine monotherapy also has evidence for effectiveness over placebo but not as much as the combination. Cheaper and more flexible dosing if the two meds are prescribed separately. 1

  • Quetiapine: Robust evidence (5 large randomized control trials) as monotherapy showing effectiveness over placebo, lithium, and paroxetine. Some evidence that it may be most effective for depression in bipolar II. Also has evidence for prophylaxis for depression and mania. 2

  • Lurasidone: Smaller evidence base but also shown to be effective. Evidence for monotherapy or as an adjunct to mood stabilizers. Expensive.

  • Cariprazine: Received FDA approval for bipolar depression in 2019. Has evidence for mania, bipolar depression, and mixed features. Currently in late-stage testing for augmentation of SSRIs/SNRIs in unipolar major depression. Expensive. At the time of this writing I personally do not have clinical experience with cariprazine.

Other Antipsychotics

  • Four negative randomized control trials are available demonstrating no efficacy for aripiprazole 3 or ziprasidone. 4

Mood Stabilizers (off-label)

  • Mood stabilizers are likely therapeutic, but the evidence is considerably smaller than that of the FDA approved antipsychotics listed above. It is recommended to confirm therapeutic drug levels of mood stabilizers as a reasonable first step for bipolar depression. Specific medications include:

  • Lithium: Evidence for bipolar depression is small and the quality of the studies have been questioned, however existing data shows it is probably effective. Also some data for prophylaxis of depressive episodes but more robust data on prevention of mania. Strong support with reduction of completed suicides and all-cause mortality. 5

  • Lamotrigine: Effective as treatment for bipolar depression as well as prevention of against further episodes. Overall the effect is modest and has had failed trials as well. A recent trial suggests robust efficacy when combined with quetiapine. 6

  • Valproic Acid (Depakote): Limited evidence for efficacy as monotherapy. One small meta-analysis of 4 randomized trials demonstrated small effect size. Many negative trials as well.

Unipolar Antidepressants (off-label)

  • Traditional antidepressants (SSRI, SNRI, TCA, MAOI, etc) may lead to "switching" to mania or hypomania in those with an underlying bipolar disorder. In fact all patients should be screened for prior manic/hypomanic episodes before starting an antidepressant.

  • Risk of "switching" when used in addition to a mood stabilizer is controversial.

  • The reality is that antidepressants are still widely used in bipolar depression, particularly breakthrough episodes occurring in patients already on mood stabilizers. SSRIs are typically recommended in this case.

  • Buproprion and paroxetine may have a lower risk of inducing mania than other unipolar antidepressants. 7

  • TCAs and venlafaxine have the highest risk of inducing mania and should generally be avoided in patients with bipolar disorder. 8

Miscellaneous Therapies

  • Pramipexole: Dopamine agonist typically used in Parkinson's disease. Two small placebo controlled studies demonstrated effectiveness in bipolar depression when combined with mood stabilizer. 9

  • Electroconvulsive therapy (ECT): Equal treatment response in unipolar vs bipolar depression. In one study ECT produced an 80% response rate with an average of 6 sessions. 10


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