When bipolar treatment fails: What’s your next step?

²¹ Other medications have shown antidepressant effects in bipolar depression (Table).^22-31 Although clinicians often use serotonin reuptake inhibitors, this practice has no empiric support in refractory bipolar depression—and our experience has not been particularly positive. Fluoxetine’s long half-life can perpetuate adverse effects long after the medication is withdrawn, and rebound depression is not uncommon when paroxetine or venlafaxine are withdrawn.

Some experts recommend discontinuing the antidepressant after depression remits to avoid driving more recurrences,³ but others do not think continuing antidepressants is risky. Apparently some patients do well with continued antidepressants, and others do not. In our experience, patients who have had mixed symptoms or mood lability are most likely to deteriorate with continued antidepressant treatment. Whenever depression returns after an initial and especially rapid response to an antidepressant, consider withdrawing the antidepressant and maximizing mood stabilizers first rather than changing or augmenting the antidepressant.

Treat seasonal symptoms. Many bipolar patients are most likely to be depressed in winter, and seasonal affective disorder is common in patients with a bipolar mood disorder. Their depression may respond to artificial bright light, usually given in the morning. Light therapy can help normalize the sleep-wake cycle, although it also can induce hypomania.

Other options. ECT is the most reliably effective treatment for bipolar depression. Because it treats both poles of the mood disorder, ECT also can be a useful maintenance treatment. A comparison of rTMS and placebo in 23 bipolar depressed patients failed to find any benefit of active treatment.³²

Table

What now? Treatment options for refractory bipolar depression

Treatment	Comment
Psychotherapy	Combine with somatic therapies for most patients with refractory mood disorders; adjunctive CBT, interpersonal and social rhythms therapy, or family-focused therapy speeded bipolar depression recovery in STEP-BD22
Bupropion	Generally accepted as first-line antidepressant; the relatively low doses used may explain this agent’s lower risk of inducing mania compared with other antidepressants
MAO inhibitors	Can be combined with carbamazepine;23 tranylcypromine is best-studied antidepressant in bipolar depression and is especially useful for anergic states;24 selegiline also can be useful
Stimulants	Stimulants—such as methylphenidate, 15 to 30 mg/d—can be rapidly effective for lethargic, anergic depression (although evidence is limited); benefit wears off rapidly if mood is adversely affected
Pramipexole	Activating dopaminergic agent with rapid onset; investigational; has produced an antidepressant effect in patients with bipolar II depression when added to mood stabilizers25
Modafinil	May be useful for residual fatigue in major depression and medication-induced sedation;26 improved depressive symptoms when used as an adjunct27
Anticonvulsants	Anticonvulsants other than lamotrigine and carbamazepine-lithium combinations are considered later choices for bipolar depression; adjunctive zonisamide has been helpful in case series;28 gabapentin, pregabalin, and topiramate also can be useful adjuncts (although not supported by controlled studies in depression); adding levetiracetam may improve response29
NMDA antagonist	Investigational; memantine30 was effective in a small controlled study, and riluzole (indicated for amyotrophic lateral sclerosis) was helpful in a small open study31
CBT: cognitive-behavioral therapy; MAO: monoamine oxidase; NMDA: N-methyl-D-aspartate; STEP-BD: Systematic Treatment Enhancement Program for Bipolar Disorder

Rapid and ultradian cycling

No controlled studies have compared single-drug or combination therapies for rapid and ultradian cycling (Box 3).³³ Thus, our recommendations for treating patients with cycling who have not responded to initial interventions are based on case series and clinical experience.

Keep a mood chart. When mood is labile, patients have difficulty recalling day to day—let alone week to week—which state predominated when. Use published mood charts or decide with the patient how to rate target symptoms such as depression, elation, irritability, increased or decreased sleep or energy, speeded up or slowed down thought, etc. Note medication changes on the chart to track whether an intervention was helpful, harmful, or neutral.

Reassess thyroid function. As many as 70% of patients with rapid cycling have subclinical hypothyroidism that contributes to mood instability.³⁴ Thyroid replacement is indicated for any degree of hypothyroidism—even if medically unimportant—in patients with refractory mood disorders.

Slowly withdraw antidepressants. Most patients with rapid cycling are taking antidepressants. If your patient is experiencing depressive symptoms while taking an antidepressant, this means the antidepressant is not working and there is little point in continuing it. For patients being withdrawn from multiple antidepressants, rotate dose decrements to help you monitor the effect of each reduction.