RESEARCH UPDATE

Experts Are Divided on the Issue, but There’s One Thing Nearly All Agree on

Antidepressants are increasingly discouraged in bipolar I disorder but what about bipolar II? Here depression is the more prominent pole, and the risk of antidepressant-induced mania is smaller. On the other hand, most of what we know about treatment comes from studies on bipolar I. Research on anti-depressants in bipolar II is scant, but a new textbook gives a rare glimpse into how the experts approach them in their practice.

In Bipolar II Disorder: Modelling, Measuring and Managing, Gordon Parker surveyed 18 international experts on their treatment strategies with bipolar II disorder.1

I’ve clustered their responses about antidepressants into 4 categories:

1 Antidepressants are helpful in bipolar II and do not cause hypomania (endorsed by 1 out of 18 experts).

2 Antidepressants are helpful in bipolar II but are best used with a mood stabilizer to avoid hypomania (endorsed by 10 out of 18 experts).

3 Antidepressants are best avoided or used with a mood stabilizer as a last resort in bipolar II (endorsed by 6 out of 18 experts).

4 Antidepressants should almost always be avoided in bipolar II because of the risk of hypomania and cycling (endorsed by 1 out of 18 experts).

That’s quite a spread, but there is one thing nearly all agreed on: antidepressants can cause hypomania, mixed states, and worsen the overall course by triggering more frequent episodes and rapid cycling. This issue has long been debated, but studies over the past decade have largely put that debate to rest.2,3

On the other hand, nearly all experts saw a role for antidepressants in bipolar II disorder. Most saw bipolar II as a more varied group than bipolar I, and within that group are some who respond to antidepressants. Even those who tended to avoid antidepressants admitted that a small minority of bipolar II patients could do well with antidepressant monotherapy.

Which antidepressants are used?

SSRIs and bupropion were the favorites, as these have the lowest risk of inducing mania. The respondents were split on the SNRIs. There is evidence that these carry a higher risk of mania, but one of them-venlafaxine-also stood out for its efficacy and safety in a small, 12-week, controlled trial where it compared favorably with lithium in bipolar II depression.4 Nearly all agreed that the tricyclics and MAOIs carried the highest risk of mania, but several acknowledged that they had had success with these agents-particularly the MAOIs-when used as a last resort.

When are antidepressants used?

In the eyes of these experts, each patient has his or her fingerprint that can guide treatment. That fingerprint is shaped by:

• The Life Chart: a visual map of manic and depressive symptoms sketched over a timeline of the patient’s life5

• Past treatment response

• Comorbidities

• Family history

• Patient preference

Antidepressants were preferred if the patient responded to them in the past or got worse after stopping them. They were also seen as a viable option when depression was long-standing, and hypomanias were mild and restricted to the distant past. Features that steered these experts away from antidepressants included a history of manic symptoms, mixed states, or rapid cycling within a few months of starting an antidepressant; rapid cycling; hypomanic or mixed symptoms within the past 6 months.

In my experience, bipolar II patients rarely have classic mania on antidepressants. It seems those drugs are just not powerful enough to flip depression into euphoria, but they can sprinkle mixed features onto the depression. In that case, the patient usually says the medication “made my depression worse.”

Hypomania is difficult to measure, both in research and practice, which partly explains the inconsistencies in this poll.

There’s also disagreement about how dangerous it is, with two basic positions:

1 Hypomania is a brief, mild, and partly desirable state that is far better than depression.

2 Hypomania leads to more depression, mixed states, and painful life consequences.

Many of my patients would agree with the second point. During hypomania, they feel they’ve lost control over their mind. It races with an anxious pressure, and they can’t turn it off to sleep. Research supports their experience. Anxiety tends to be even higher in hypomania than it is in depression, and the most common chief complaint during manic states is surprisingly, depression.6,7

I’m reluctant to risk that painful state with an antidepressant, especially when we have so many other options for bipolar depression. When I do use antidepressants in bipolar II, I rarely see recovery but do see some response about 25% of the time. The more difficult question is whether that response was a placebo effect and whether it came with an added cost of rapid cycling. To answer that, I’ll attempt a taper after the patient’s life and moods have stabilized for about 6 months, slowly lowering the dose of the antidepressant over a 2- to 4-month period to see if it’s necessary.

This article was originally published on April 16, 2019 and has since been updated.

Disclosures:

Dr Aiken does not accept honoraria from pharmaceutical companies but receives honoraria from W.W. Norton & Co. for Bipolar, Not So Much, which he coauthored with Jim Phelps, MD.

Dr Aiken is Director of the Mood Treatment Center, Editor in Chief, The Carlat Psychiatry Report, and Instructor in Clinical Psychiatry, Wake Forest University School of Medicine. He is the Bipolar Disorder Section Co-Editor for Psychiatric Times.

References:

1. Parker G, Ed. Bipolar II Disorder: Modelling, Measuring, and Managing, 3rd ed. Cambridge, UK: Cambridge University Press; 2019.

2. Viktorin A, Lichtenstein P, Thase ME, et al. The risk of switch to mania in patients with bipolar disorder during treatment with an antidepressant alone and in combination with a mood stabilizer. Am J Psychiatry. 2014;171:1067-1073.

3. Fornaro M, Anastasia A, Novello S, et al. Incidence, prevalence and clinical correlates of antidepressant-emergent mania in bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2018;20:195-227.

4. Amsterdam JD, Lorenzo-Luaces L, Soeller I, et al. Short-term venlafaxine v. lithium monotherapy for bipolar type II major depressive episodes: effectiveness and mood conversion rate. Br J Psychiatry. 2016;208:359-365.

5. Bipolar Network News. Life Charting for Patients. www.bipolarnews.org/?page id=175. Accessed April 12, 2019.

6. Simon NM, Otto MW, Fischmann D, et al. Panic disorder and bipolar disorder: anxiety sensitivity as a potential mediator of panic during manic states. J Affect Disord. 2005;87:101-105.

7. Kotin J, Goodwin FK. Depression during mania: clinical observations and theoretical implications. Am J Psychiatry. 1972;129:679-786.