Evidence-Based Reviews

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

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Be a troubleshooter: systematically eliminate whatever is perpetuating manic, depressive, or cycling symptoms.



All phases of bipolar disorder can be difficult to treat, and patients remain symptomatic on average about half the time.1 Not all bipolar patients who experience continued illness and disability are treatment-resistant (Box 1), but when symptoms persist you may ask yourself: Was treatment suboptimal or simply ineffective?

Patients with severe symptoms may be satisfied with a substantial decrease in symptoms, but any residual symptoms cause ongoing distress and lower the threshold for recurrences.2 Finding the right combination of therapies for your patient is key to achieving an enduring response.

Future studies may tell us which treatments to combine and in what sequence for complex bipolar disorder, but—since most published studies exclude complex and comorbid cases—for now we must rely on limited controlled data and clinical experience. Using those resources, we offer comprehensive, practical recommendations for trouble-shooting (Box 2)3-6 and getting better results when bipolar disorder does not respond to standard treatment.

Box 1

What is ‘treatment resistance’ in bipolar disorder?

Some studies define treatment resistance as failure to respond to lithium, and in other settings it is viewed as failure to respond to ≥2 treatment courses. Because euthymia and normal functioning are important for long-term prognosis, we define treatment-resistance as failure to achieve both symptomatic and functional remission following an adequate course of therapy.

Effective strategies for treating bipolar disorder depend on:

  • illness phase (later episodes are more difficult to treat than earlier ones)
  • symptom complexity (mixed symptoms probably reflect more complex pathophysiology and are more likely to require combination therapies)
  • predominant presentations (mania, depression, rapid and ultradian cycling)
  • whether symptoms are acute or chronic.

Unfortunately, the findings of and strategies used in clinical trials of refractory bipolar disorder are difficult to extrapolate to everyday practice. Most studies exclude patients with a history of treatment resistance, severe symptoms, and important comorbidities such as substance abuse. In addition, the usual primary endpoint is response (≥50% reduction of symptoms) rather than remission (minimal symptoms and no longer meeting criteria for the disorder). Very few studies address functional remission, which is necessary to reduce the risk of symptomatic recurrence.

In clinical practice, when initial treatment for bipolar disorder fails to produce remission, systematically addressing 5 questions (Box 2) can help direct your next step.


When a patient with mania does not respond as expected, the next step depends on which antimanic agent you prescribed:

Lithium can take a month to become fully effective for mania, which is why a benzodiazepine or antipsychotic is often added acutely to reduce agitation. Do not mistake neurotoxic interactions between lithium and antipsychotics for increased mania.

Although data vary on lithium’s optimal serum level, adjust to approximately 0.8 to 1 mEq/L, if tolerated, when lower levels are not effective. Children and young adolescents may need higher serum levels (such as 1.5 mEq/L) because the difference between serum and brain lithium levels is greater in younger patients than in adults.

Consider the dosing schedule. Because lithium’s elimination half-life with repeated dosing is 24 hours, most adults can take any formulation once daily—which improves adherence and reduces adverse effects. Children eliminate lithium more rapidly and need more frequent dosing.

Valproate. Empiric trials in bipolar disorder or epilepsy do not support the frequently reported “therapeutic range” of 50 to 125 μg/mL. Pooled data from three 21-day, double-blind studies of valproate in mania show a linear relationship between serum level and clinical response, with the most beneficial response at >94 μg/mL.7 Better results—but more side effects—are seen with levels >100 μg/mL.

High loading doses result in more rapid control of agitation, probably as a result of sedation. In our experience, however, rapidly sedating patients may interfere with long-term adherence.

Carbamazepine, other anticonvulsants. Because they less sedating, carbamazepine and other anticonvulsants might not appear to be rapidly effective for bipolar mania. If you wait up to a month, however, any antimanic effect will be obvious.

Antipsychotics are rapidly effective for mania. Higher doses work faster but produce more side effects. After an acute response, some patients can be maintained on a second-generation antipsychotic (SGA), but others do better on a standard mood stabilizer such as lithium or valproate.

Calcium channel blockers. Verapamil has been effective mostly for lithium-responsive mania in 27 of 30 studies. Nimodipine has been useful for more complex bipolar syndromes in a few studies using patients as their own controls.

To be effective for bipolar disorder, however, calcium channel blockers require frequent, high dosing (such as verapamil, 120 mg 4 times daily, or nimodipine, 60 to 120 mg 6 times daily), which makes adherence difficult.


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