Bipolar Disorder & Pharmacologic Treatment for Depression

Other Medication Options

Lithium is an old and effective standby; it works rapidly and is substantially less expensive than the medications listed above, and it’s the only agent discussed here found to substantially decrease risk of suicide. It is listed as first-line treatment for acute bipolar depression in the APA practice guidelines (although these have not been updated since 2002). See our January 2011 issue of TCPR for a primer on the use of lithium, as well as the interview “Diagnosis and Treatment of Bipolar Disorder” on p. 1.

So why is lithium only approved by the FDA for acute mania and bipolar maintenance, not acute depressive episodes? Part of the answer might simply be money. Obtaining FDA approval requires substantial time and effort, almost always invested by the drug’s manufacturer. Because lithium has been a generic medication for many years and because it is already used in bipolar disorder, there is little incentive for anyone to seek approval for a specific indication such as bipolar depression.

In a 1993 review of lithium for bipolar depression, eight of nine placebo controlled studies were positive (Zornberg GL & Pope HG Jr, J Clin Psychopharmacol 1993;13(6):397–408). Since then, there haven’t been many studies of lithium’s utility in bipolar depression.

One negative result of lithium was in the EMBOLDEN I trial (Young AH el al, J Clin Psychiatry 2010;71(2):150–162), in which lithium pretty much tanked for bipolar depression—not only did it perform worse than quetiapine, it also did not separate from placebo on the MADRS. However, note that the study was sponsored by quetiapine’s manufacturer, and the mean serum concentration of lithium was on the low end (0.61 mEq/L), just a hair within the clinically acceptable range of 0.6 to 1.2 mEq/L, and below the concentration that is often needed for efficacy in practice.

Lamotrigine (Lamictal) is a popular choice, primarily because of its lack of side effects relative to other treatments for bipolar disorder, and because, in my experience, it seems to keep people on the “happy” side of the mood spectrum, which is appreciated by patients who feel dulled on traditional mood stabilizers. Although data are mixed for acute bipolar depression, it does appear at least to be good at preventing future episodes, and is FDA-approved for maintenance treatment (Amman B et al, J Psychopharmacol 2011;25(10):1289–1294). However, it appears to have less efficacy for preventing mania. For this reason, I tend to use it only in combination with another moodstabilizing agent.

Antidepressants. While there is little evidence supporting the use of antidepressants in bipolar depression, they are used quite frequently, particularly as adjuncts to a mood stabilizer. There are two issues that arise in the use of antidepressants in these patients: first, do they precipitate mania, and second, do they work to alleviate depression? The first issue remains controversial. Several studies have demonstrated that bipolar patients taking antidepressants do not switch into mania, but many of these were confounded by the patients taking mood stabilizers at the same time. For instance, the large and well-designed STEP-BD study found that neither bupropion nor paroxetine precipitated mania, although all patients were also on antimanic medication during the trial (Sachs GS et al, N Engl J Med 2007;356(17):1711–1722). Regarding efficacy, the same study showed no benefit of these medications in bipolar depression. That is not to say there are no outlier patients who will still benefit from an antidepressant during a bipolar depressive episode (see, for instance, Gijsman HJ et al, Am J Psychiatry 2004;161(9):1537–1547). However, for most bipolar patients, antidepressants are unlikely to provide much efficacy.

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We’ve covered this very involved topic in prior issues of TCPR [see the July/August 2012 issue] and we will surely revisit it sometime soon.

Other Mood Stabilizers and Antipsychotics. Beyond those listed above, many of us have tried other mood stabilizers and atypical antipsychotics to treat our patients with bipolar depression. There is some evidence for valproate as monotherapy, but others are either inadequately studied or yield conflicting results (see Selle V et al, Pharmacopsychiatry 2014; 47(2):43–52 for a meta-analysis and review). Aripiprazole (Abilify) has been effective as an adjunct to a mood stabilizer for minor depressive symptoms in an open-label trial (Schweitzer I et al, Int J Bipolar Disorders 2013;1(1):4) but was not effective as monotherapy for bipolar depression in two placebocontrolled studies (Thase ME et al, J Clin Psychopharm 2008;28(1):13–20).

TCPR VERDICT: Which meds for bipolar depression? If you’re into FDA approval, lurasidone’s your best choice—you’ll likely avoid the potential metabolic effects of the other approved drugs. Off-label options include lithium and lamotrigine. And while not generally advised by experts or supported by the evidence, antidepressants are still used by many: just be sure to proceed with caution.

Recommended Metabolic Screening for Patients Taking Antipsychotics

If your patient is taking an antipsychotic with a risk of causing weight gain, especially olanzapine and quetiapine, but including risperidone and some others, you should regularly check for the possibility of metabolic side effects. The chart below is from guidelines developed in 2004 by the American Psychiatric Association (APA) and American Diabetes Association (ADA) (American Diabetes Association et al, Diabetes Care 2004;27(2):596–601):

Recommended Metabolic Screening Patients Taking Antipsychotics

FDA-Approved Medications for Bipolar Disorder

Bipolar Disorder & Pharmacologic Treatment for Depression

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This article was published in print 11 & 12/2014 in Volume:Issue 12:11.


APA Reference
Berlin,, R. (2016). Bipolar Disorder & Pharmacologic Treatment for Depression. Psych Central. Retrieved on June 17, 2019, from


Scientifically Reviewed
Last updated: 26 Jan 2016
Last reviewed: By John M. Grohol, Psy.D. on 26 Jan 2016
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