Antidepressants in Bipolar Depression

In a recent systematic review it is concluded that with the limited number of studies and their methodological limitations no evidence was found supporting the notion that antidepressants can induce switching or accelerate cycling. In terms of switch risk, antidepressants seem safe when combined with a mood stabilizer. However, antidepressants given as monotherapy cannot be recommended, at least not when treating patients with bipolar disorder type 1.

However, it should be noted that stating that there is no evidence for such a risk is obviously not the same as stating that there is evidence for no such risk. Nevertheless, there is some evidence suggesting that antidepressants given in addition to a mood stabilizer are not associated with an increased rate of switch when compared with the rate associated with the mood stabilizer alone…

With switch was meant the switch of depression into hypomania⁄ mania in patients with bipolar disorder on antidepressants. In this meta analysis this question was opposed against the probability that this switch is a phenomenon attributable to the natural history of bipolar disorder itself.

Now why is that important?
Antidepressants have been poorly studied for their use in bipolar depression. The main reason for this is that, most of the evidence base in clinical psychopharmacology comes from industry-sponsored trials.
The industry couldn’t find any advantage for an antidepressant being registered for depression in bipolar disorder. They could be used for depression and they could promote antidepressants for any kind of depression.
Moreover, antidepressants are the most commonly prescribed drugs in bipolar disorder, way ahead of mood stabilizers and antipsychotics, despite the evidence base is much better for the latter.

A Psychiatric Divide?
The European point of view is that the switch is not promoted by the use of antidepressants but more probably the course of the illness while the more defensive standpoint of the view in the United States is that switches are caused mainly by antidepressant use in bipolar depressive patients especially tricyclic antidepressants.

More findings from this meta analysis

• Switch rates in unipolar depressed patients were, respectively, 3.0% and 4.6%, before and after the introduction of antidepressants; in bipolar depressed patients, similar rates of around 29% were observed for the two periods.
• In five trials comparing placebo with an antidepressant in bipolar depression the pooled total switch rates when on treatment with antidepressants and placebo were 3.8% and 4.7%, respectively, and not statistically significant.
• When combining a mood stabilizer and an antidepressant compared to a mood stabilizer alone or placebo the switch rates between moodstabilzer alone or the combination with an antidepressant did not differ significantly.
• The likelihood of switching into hypomania ⁄mania is dependent on the course of depressive symptoms: a patient who has remitted from depression seems to be at a higher risk of switching than a patient with persistent depressive symptoms. Therefore, the higher switch rates observed with TCAs might be simply a methodological artefact explained by a higher efficacy of TCAs.
• Data on switching after a symptom free interval are even more limited in bipolar disorder.
• Depressed patients with bipolar disorder type 2 given an antidepressant and a mood stabilizer might have a lower switch rate than patients with bipolar disorder type 1 receiving the same treatment.
• Very high switch rates of up to 50% during ECT are reported; this high rate may be
  linked to the high antidepressant efficacy of ECT. The advantage of ECT is that continuing the treatment treats the resulting hypomania/mania.
• The association between rapid cycling and antidepressant use might be explained by the fact that included patients sought treatment for depression which has been found to be a predictor of rapid cycling. Systematic data on any causal role of antidepressants in the development of rapid cycling
  are lacking.

The only solution to finding a definite answer to the question whether antidepressants can induce hypomania/mania and rapid cycling in bipolar depressed patients is doing a randomized placebo controlled trial.

Why is a placebo controlled trial not feasible?
The sample size needed to control for the natural course of the bipolar disorder would make a very large sample necessary. Moreover, the treatment groups then may not be balanced any more in terms of baseline clinical variables such as number of previous episodes or previous rapid cycling.

Even if antidepressants could be found to induce switches to a larger extent than other treatments, then it might be that the total burden of illness due to shortening of total duration of depression would be diminished.

In the same number of the Acta Psychiatrica Scandinavia results of another meta-analysis was published. Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks.

In short the main conclusions were:

• Available research suggests an unfavorable risk ⁄ benefit relationship for long-term antidepressant treatment in type-I bipolar disorder.
• Adding an antidepressant to a mood stabilizer has yielded little gain in protection from recurrences of bipolar depression.
• Antidepressant-alone, without a mood stabilizer, may diminish depressive relapse, but carries larger risks of manic or hypomania relapses.

R. W. Licht, H. Gijsman, W. A. Nolen, J. Angst (2008). Are antidepressants safe in the treatment of bipolar depression? A critical evaluation of their potential risk to induce switch into mania or cycle acceleration Acta Psychiatrica Scandinavica, 118 (5), 337-346 DOI: 10.1111/j.1600-0447.2008.01237.x

S. N. Ghaemi, A. P. Wingo, M. A. Filkowski, R. J. Baldessarini (2008). Long-term antidepressant treatment in bipolar disorder: meta-analyses of benefits and risks Acta Psychiatrica Scandinavica, 118 (5), 347-356 DOI: 10.1111/j.1600-0447.2008.01257.x