The high relapse rate in patients taking mood stabilizers—with or without an antidepressant—and the Ghaemi et al data3 suggest that we need alternate antidepressant approaches to bipolar depression. Potential regimens—anticonvulsants, atypical antipsychotics, and other agents—merit further study. So far the evidence is mixed, and the most effective approaches are not well-delineated.
Anticonvulsants. Sachs et al4 reported that adding lamotrigine or lamotrigine plus an antidepressant to mood stabilizer therapy did not appear more effective in treating bipolar depression than simply maintaining the mood stabilizers.
Similarly, a small randomized, double-blind study in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was stopped early because of low total response. Adjunctive lamotrigine (24%) and inositol (17%) appeared more effective than risperidone (5%) for refractory bipolar depression.
Antipsychotics. In an 8-week randomized trial by Tohen et al,5 833 patients with moderate to severe bipolar I depression were treated with olanzapine, olanzapine plus fluoxetine, or placebo. Core depression symptoms improved significantly more with olanzapine alone or with fluoxetine compared with placebo, as measured by mean changes in the Montgomery-Asberg Depression Rating Scale.
In a 6-month open trial, 192 patients whose bipolar I depression remitted with any of the three treatments6 continued olanzapine and then, if needed after the first week, the olanzapine/fluoxetine combination (OFC). Nearly two-thirds of patients (62%) remained without a depressive recurrence, and 94% remained without a manic recurrence while taking the OFC. These unpublished data indicate that the OFC provided greater prophylactic antimanic than antidepressant effects.
Calabrese et al7 recently presented unpublished data comparing the effects of quetiapine monotherapy, 300 or 600 mg/d, with placebo in patients with bipolar depression. Beginning in the first week of treatment, both quetiapine dosages produced significantly greater antidepressant, antianxiety, and anti-insomnia effects than placebo (P < 0.001). Remission rates with both dosages were >50%.
Summary. These first controlled studies of atypical antipsychotics in bipolar depression suggest that this drug class may have antidepressant as well as their demonstrated antimanic effects.
Recommendations—for now
Controlled clinical trials have not been conducted, and the evidence on using adjunctive antidepressants in bipolar depression is ambiguous.8-11 As a result, it is unclear when or how long to use antidepressants, and many of the inferences and suggestions in this paper remain highly provisional.
Initiating antidepressants. My personal treatment guidelines—and those of many other clinicians—are to use the unimodal antidepressants to augment mood stabilizers in bipolar patients experiencing breakthrough depression, as long as they have not had:
- ultra-rapid cycling (>4 episodes/week)
- antidepressant-induced cycle acceleration
- or multiple episodes of antidepressant-induced mania, despite co-treatment with mood stabilizers.
If any of these variables is present, I would instead add another mood stabilizer or an atypical antipsychotic.
Continuing antidepressants. If the patient remains stable for 2 months after the antidepressant is added—with no depression or manic occurrence—I would continue the antidepressant indefinitely, based on the Altshuler et al data.12
Mood charting.I also recommend that clinicians help patients develop an individual method for mood charting, such as that used in the National Institute of Mental Health Life Chart Method (NIMH-LCM)12,13 or the STEP-BD program.14 Goals of the 5-year STEP-BD are to:
- determine the most effective treatments and relapse prevention strategies for bipolar disorder
- evaluate the psychotropic benefit of anticonvulsants, atypical antipsychotics, cholinesterase inhibitors, and neurotransmitter precursors
- determine the benefit of psychotropic combinations.
Mood charts can provide a retrospective and prospective overview of a patient’s illness course and response to medications. Compared with patient recall, mood charts help clinicians evaluate more precisely the risk of switching and the risks and benefits of starting, continuing, or discontinuing antidepressants. Mood charts may be your most effective tool for managing a patient’s bipolar depression and achieving and maintaining long-term remission.
Summary. In the absence of consensus or guidelines for treating bipolar depression, I suggest:
- a conservative approach—ie, no changes in medication—when the patient remains well on a given regimen
- an aggressive—if not radical—series of treatments and revisions when the illness course remains problematic.
Many medication classes and adjunctive strategies are available for treating bipolar illness.15-18 I recommend that you continue to systematically explore adjunctive treatments and combinations until the patient improves or—even better—attains remission. Good response can be achieved—even in treatment-refractory patients ill for long periods or with recurrent bipolar depression—although complex combination therapy is often required.
Related resources
- National Institute of Mental Health-Life Chart Method. Retrospective and prospective mood-tracking charts for patients with bipolar disorder. www.bipolarnews.org
- Systematic Treatment Enhancement Program for Bipolar Depression (STEP-BD). National Institute of Mental Health. www.stepbd.org/research/
Drug brand names
- Fluoxetine • Prozac
- Lamotrigine • Lamictal
- Olanzapine • Zyprexa
- Olanzapine/fluoxetine • Symbyax
- Quetiapine • Seroquel
- Risperidone • Risperdal