Antidepressants in Bipolar I Disorder: Never as Monotherapy

Why were up to 35% of the patients with bipolar disorder in the Swedish registry treated with antidepressant monotherapy? Why are 15% of manic patients maintained on antidepressants despite the emergence of manic symptoms (6)? Why are serotonin-norepinephrine reuptake inhibitors so widely used (7) despite their reportedly having a greater risk of inducing mania than selective serotonin reuptake inhibitors (9, 10)? Why are so many patients with mixed states treated with antidepressants (11)? There may be several answers to these questions. First, it may simply be that antidepressants actually work. In fact, the evidence that they work is as weak as the evidence that they do not. The absence of financial incentives to seek a bipolar disorder indication (given that marketed antidepressants all have an indication in major depression, and the diagnostic cross-sectional criteria are the same for unipolar and bipolar depression), as opposed to the case for antipsychotics or anticonvulsants, has hindered research on these particular compounds for bipolar disorder. Second, the extensive use of antidepressants may be the result of limited treatment options, safety concerns about overuse of antipsychotics, extrapolation of antidepressant efficacy in other indications, and perhaps pressure from patients themselves asking for rapid relief of the unbearable pain of depression.

The Viktorin et al. Swedish registry study quite strikingly confirms early findings that antidepressant monotherapy is potentially harmful in bipolar disorder (12). Patients should be advised that without the addition of a mood stabilizer, there is a serious risk of manic switch. The study does not resolve the question of whether antidepressants should be used at all. Research progress has yielded several alternatives to antidepressants, with better evidence of efficacy, albeit far from ideal tolerability (13). In the current situation, it is truer than ever that every patient is a unique case deserving an individualized approach. Every patient should have the right to receive a detailed summary of reasonable treatment choices, psychoeducation on the illness, and objective information on the benefits and risks of each strategy. For many patients, antidepressants will not be the first-line recommendation, but perhaps those with a depressive-predominant polarity, with bipolar II disorder, or with a previous response to antidepressants may be candidates for an adjunctive antidepressant (1, 14–16). For patients with a history of mixed states and switching, with rapid cycling, or with a mania-predominant polarity, we may want to avoid prescribing antidepressants at all costs (1). We may want to look at comorbidities, especially those that may respond to antidepressant therapy, before we decide what to prescribe. Entering the era of personalized medicine, which in psychiatry at this point means stratifying patients according to clinical profile (17, 18), we want better evidence for what to do in patient subgroups, rather than simple registration trials that speak about the drug but not about the patients. As mentioned earlier, if excellent treatments were available for bipolar disorder, this editorial would not make sense, and therefore any effort to develop and market novel drugs must be applauded. Quetiapine, lurasidone, the combination of olanzapine and fluoxetine (an antidepressant!), and ECT are evidence-based treatment options (13), but it is obvious that many patients need something else. That “something else,” at present, is what their physician or treatment team may figure out, after a careful investigation of the individual patient’s needs and profile, from a number of available options, including adjunctive antidepressants. And the recipe is still the same: scientific knowledge, experience, empathy, and above all, common sense.