Question. I have read reports that antidepressants prescribed for patients in the depressed phase of cyclothymic or bipolar II illness can (a) shorten the cycles of the illness (b) possibly lead to refractory depression in the long run and (c) precipitate hypomanic episodes. Are you aware of any data on these issues? Do you know of any information on alteration of other aspects of the course of mild bipolar illness? Finally, is there any consensus in the field regarding the appropriate treatment of depressed phases of mild bipolar illness?

Answer. I suggest you read (if you haven’t already) Akiskal’s article in the April 1994 Journal of Clinical Psychiatry (suppl), on dysthymic and cyclothymic depression, as well as the study by Altshuler et al in the August 1995 American Journal of Psychiatry.

There is still a fair amount of controversy as to whether antidepressants can affect cycle length or “switching” in bipolar illness; and if so, how much and in which subtypes of bipolar disorder. The consensus seems to be – and I concur with this–that at least some bipolar patients are sensitive to antidepressants, particularly tricyclics, and that their course can worsen substantially with use of these agents.

As early as 1977, Akiskal and colleagues found that Tricyclic Antidepressants (TCAs) given over 6 weeks doubled the rate of hypomania in predominantly depressed cyclothymic patients. Akiskal’s group supports the notion that patients with “soft” indicators of bipolar illness may be particularly susceptible to the mood destabilizing effects of TCAs. (They think trazodone and trimipramine may be less noxious, perhaps because these agents are less disruptive of sleep.) On the other hand, Himmelhoch has data showing that the Monoamine Oxidase Inhibitor (MAOI) tranylcypromine (in comparison with imipramine) may be useful in “anergic” bipolar depression, with only brief, mild hypomania associated with use.

Similarly, some data suggest that bupropion has less likelihood of promoting cycling in “soft bipolar depressives,” usually when used in concert with a mood stabilizer. Akiskal believes that in bipolar II patients, it is best to use “conservative” doses of MAOIs, bupropion, or Selective Serotonin Reuptake Inhibitors (SSRIs), and to stay away from TCAs. This is close to my own view, though I have seen and treated some bipolar patients who did fine for many years on tricyclics (in combination with mood stabilizers) and could not maintain mood stability without the TCA – but some of these cases were treated before the availability of newer agents. Altshuler et al also found that antidepressant-induced cycle acceleration (but not induced mania) is associated with female gender and type II bipolarity.

With respect to any consensus on the treatment of mild bipolar illness, I would offer my own summary: avoid antidepressants of any kind if possible; use lithium (actually a pretty good antidepressant) as the mainstay of treatment unless there are “mixed” or dysphoric features (in which case, I’d use valproate); and when forced to treat depression, start with low doses (37.5 mg/day) of bupropion. It’s also important to rule out borderline hypothyroidism in rapid cyclers. Thyroxine may, in my experience, be useful not only as a mood stabilizer, but as a mild antidepressant in some bipolar depressed patients.