Evidence-Based Reviews

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

Current Psychiatry. 2008 January;7(1):39-46

References

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9. Pazzaglia P, Post RM, Ketter TA, et al. Nimodipine monotherapy and carbamazepine augmentation in patients with refractory recurrent affective illness. J Clin Psychopharmacol 1998;18:404-13.

10. Conway CR, Chibnall JT, Nelson LA, et al. An open-label trial of adjunctive oxcarbazepine for bipolar disorder. J Clin Psychopharmacol 2006;26:95-7.

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Box 2

5 questions to consider when bipolar symptoms persist

1 Is the patient taking anything that is making symptoms worse?

Antidepressants can induce mania, hypomania, and cycle acceleration in bipolar disorder, even when mood stabilizers are co-prescribed.³ Stimulants also may destabilize bipolar mood disorders; consider this possibility when patients taking stimulants for apparent attention-deficit/hyperactivity disorder at first appear to improve and then deteriorate.

Alcohol and cocaine can induce mania and depression. Cocaine is a potent kindling stimulus that could contribute to enduring mood instability.

2 Is the patient taking the medication?

Treatment adherence by bipolar patients may be as low as 35%.⁴ Ask outpatients what kinds of problems they have encountered taking medications, not whether they have such problems. Talk with the patient about adherence after each dosage increase, and be readily available. Prescribe extended-release pills for patients who have trouble keeping track of medications.

3 Is treatment adequate?

Adjust mood-stabilizer dosing until the patient responds or cannot tolerate the medication; complex cases often require combination treatment. Give the medication sufficient time to work; most mood stabilizers take ≥1 month to become fully effective.

4 Is another condition interfering with treatment?

Up to 70% of patients with refractory mood disorders have subclinical hypothyroidism. Look for:

elevated thyroid stimulating hormone (TSH) with or without decreased thyroxine (T4)
elevated TSH response to thyrotrop-inreleasing hormone (TRH).⁵

Also consider hypercalcemia from chronic lithium therapy,⁶ anemia, sleep apnea, posttraumatic stress disorder, substance use disorders, and personality disorders.

5 Am I ignoring psychotherapy?

Address psychosocial issues that influence the course of illness. Attend to patients’ important relationships, loss, negative thinking, and biological and social rhythms.

Augment or switch? If mania does not respond to an adequate dose of an antimanic drug given for a sufficient time, the next question is whether to augment or switch treatments. No studies have compared augmenting vs switching in any bipolar disorder phase, but it seems reasonable to:

consider augmentation first when a patient has had a partial response to a given medication
switch when a patient cannot tolerate or shows no response to a therapeutic dose of a given medication.

Combinations. Benzodiazepines such as clonazepam, 2 to 6 mg/d, or lorazepam, 4 to 8 mg/d, are often used to control agitation and insomnia in mania, usually as adjuncts to mood stabilizers (although improved sleep by itself can ameliorate acute mania in some cases). Adding an SGA may help when mania responds partially to a mood stabilizer.⁸

Clinical Point

Give medication sufficient time to work; most mood stabilizers take ≥1 month to become fully effective

Combinations of lithium and carbamazepine or valproate can be more effective than either drug alone, but therapeutic doses of each usually are needed. Carbamazepine has been used successfully to augment a partial response to nimodipine.⁹ In a small open-label trial, adding oxcarbazepine to lithium, valproate or antidepressants improved response in some patients with mild refractory mania.¹⁰

Switching among anticonvulsants can be useful because their actions and side effects differ. Clozapine in a wide range of doses can be very effective for refractory mania,¹¹ but its use is difficult to monitor in highly agitated manic patients.

Other options. Electroconvulsive therapy (ECT) is the most effective treatment for mania, producing higher response rates than any antimanic drug.¹² In a study of repetitive transcranial magnetic stimulation (rTMS), 8 of 9 patients with mania refractory to mood stabilizers had a sustained response after 1 month of right-sided rTMS treatment.¹³ Conversely, left-sided rTMS can aggravate mania.

Bipolar depression

Continuing controversy about the best way to treat bipolar depression makes it difficult to know if treatment has been suboptimal or a patient is treatment-resistant.

Antidepressants. No antidepressant is approved (or recommended) as monotherapy for bipolar depression, and most experts recommend against prescribing antidepressants without concomitant mood stabilizers. Even so:

Clinicians prescribing monotherapy for bipolar disorder choose antidepressants twice as often as mood stabilizers.
Antidepressants are prescribed more frequently in combination with mood stabilizers than as monotherapy, although empiric trials have shown most antidepressants are not effective for bipolar depression.¹⁴

A recent report from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study¹⁵ found that adding bupropion or paroxetine to mood stabilizers was no more effective than adding placebo. Rates of mania induction also were no greater with antidepressants than with placebo, but the study lasted only 8 weeks. One interpretation of this finding is that when antidepressants do not induce mania and cycling, they also do not improve bipolar depression.

Clinical Point

Electroconvulsive therapy is the most effective treatment for mania, producing higher response rates than any drug