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When bipolar treatment fails: What’s your next step?
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.
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.
Mania
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.
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.
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.
- 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 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
In many cases, an antidepressant seems to help at first and then induces a recurrence of depression, often mixed with dysphoric hypomanic symptoms. The recurrent episode improves when the clinician increases the antidepressant dose or changes to another antidepressant, only to be followed by another recurrence that may be interpreted as an incomplete antidepressant response.
Antipsychotics. Quetiapine16 and a combination of olanzapine and fluoxetine17 are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.
Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.
Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.
Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.
No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:
Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.18
Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.
Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.
Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.20 Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.
Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.
Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.
Approximately 20% of bipolar patients are thought to experience rapid cycling, defined as ≥4 affective episodes/year separated by at least 2 weeks of euthymia between poles or with an immediate switch from one pole to the other.32 The prevalence of ultradian cycling—in which multiple brief affective episodes (usually subsyndromal or mixed) occur each day—is unclear.
Both cycling types probably represent stages in the evolution of bipolar mood disorders rather than distinct diagnoses. In many cases, mood cycling abates after months to years, but morbidity can be high and the wrong treatment may perpetuate mood cycling.
Complex mood cycling rarely responds to a single treatment, probably because its pathophysiology is complex. The need for polypharmacy may create the impression of treatment failure, but no one would expect a single medication to be sufficient for other complex illnesses such as cancer or AIDS.
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.
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.
Combine mood stabilizers. After optimizing the dose of a single mood stabilizer, add a second one from a different class. In an open trial, adding oxcarbazepine, up to 2,400 mg/d, helped approximately one-third of 20 patients with refractory mood cycling.10 Lithium is generally considered less effective than anticonvulsants in rapid cycling, but at least one study showed it was equivalent to carbamazepine for this problem.35 Lithium combined with other mood stabilizers may be more effective than lithium monotherapy in refractory bipolar states.
Other options to consider in combination with mood stabilizers:
- an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
- clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states36 (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
- nimodipine, which has empiric support for complex mood cycling37 and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
- supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens34 (but risks of inducing hyperthyroidism make this intervention third-line).
Related resources
- Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
- Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
- Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
- Bupropion • Wellbutrin
- Carbamazepine • Tegretol
- Clonazepam • Klonopin
- Clozapine • Clozaril
- Fluoxetine • Prozac
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Levetiracetam • Keppra
- Lithium • Lithobid, others
- Lorazepam • Ativan
- Memantine • Namenda
- Methylphenidate • Concerta, Ritalin, others
- Modafinil • Provigil
- Nimodipine • Nimotop
- Olanzapine/fluoxetine • Symbyax
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Pramipexole • Mirapex
- Pregabalin • Lyrica
- Quetiapine • Seroquel
- Riluzole • Rilutek
- Selegiline • Eldepryl
- Topiramate • Topamax
- Tranylcypromine • Parnate
- Valproate • Depakene, Depakote
- Venlafaxine • Effexor
- Verapamil • Calan, Isoptin, others
- Zonisamide • Zonegran
Dr. Mostert reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.
1. Judd JL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;61:261-9.
2. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEPBD). Am J Psychiatry 2006;163:217-24.
3. Altschuler LL, Post RM, Leverich GS. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995;152:1130-8.
4. Osterberg L, Blaschke T. Drug therapy: adherence to medication. N Engl J Med 2005;353:487-97.
5. Kusalic M. Grade II and grade III hypothyroidism in rapid cycling bipolar patients. Biol Psychiatry 1992;25:177-81.
6. Franks RD, Dubovsky SL, Lifshitz M, et al. Long-term lithium carbonate therapy causes hyperparathyroidism. Arch Gen Psychiatry 1982;39:1074-7.
7. Allen MH, Hirschfeld RMA, Wozniak PJ, et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 2006;163:272-5.
8. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially responsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.
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.
11. Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J Psychiatry 1996;153:759-64.
12. Mukherjee S, Sackeim HA, Schnur DB. Electroconvulsive therapy of acute manic episodes: a review of 50 years’ experience. Am J Psychiatry 1994;151:169-76.
13. Michael N, Erfurth A. Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation. J Affect Disord 2004;78:253-7.
14. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 2007;58:85-91.
15. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007;356:1711-22.
16. Cookson J, Keck PE, Jr, Ketter TA, Macfadden W. Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study. Int Clin Psychopharmacol 2007;22(2):93-100.
17. Tohen M, Vieta E, Calabrese JR, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079-88.
18. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry 2002;159:116-21.
19. Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet 2007;369:935-45.
20. Kishimoto A. The treatment of affective disorder with carbamazepine: prophylactic synergism of lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:483-93.
21. McElroy SL, Zarate CA, Cookson J, et al. A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. J Clin Psychiatry 2004;65:204-10.
22. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64:419-26.
23. Ketter TA, Post RM, Parekh PI, Worthington K. Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. J Clin Psychiatry 1995;56:471-5.
24. Himmelhoch JM, Thase ME, Mallinger AG, Houck PR. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991;148:910-6.
25. Zarate CAJ, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004;56:54-60.
26. Lam JY, Freeman MK, Cates ME. Modafinil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants. Ann Pharmacother 2007;41:1005-12.
27. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007;164:1242-9.
28. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry 2005;66:195-8.
29. Post RM, Altshuler LL, Frye MA, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry 2005;66:370-4.
30. Zarate CAJ, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64.
31. Zarate CAJ, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005;57:430-2.
32. Nahas Z, Kozel FA, Li X, et al. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003;5:40-7.
33. Schneck CD. Treatment of rapid-cycling bipolar disorder. J Clin Psychiatry 2006;67(suppl 11):22-7.
34. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder, I: Association with grade I hypothyroidism. Arch Gen Psychiatry 1990;47:427-32.
35. Okuma T, Yamashita I, Takahashi R, et al. Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry 1990;23:143-50.
36. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 1991;11:396-7.
37. Goodnick PJ. Nimodipine treatment of rapid cycling bipolar disorder. J Clin Psychiatry 1995;56:330.-
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.
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.
Mania
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.
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.
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.
- 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 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
In many cases, an antidepressant seems to help at first and then induces a recurrence of depression, often mixed with dysphoric hypomanic symptoms. The recurrent episode improves when the clinician increases the antidepressant dose or changes to another antidepressant, only to be followed by another recurrence that may be interpreted as an incomplete antidepressant response.
Antipsychotics. Quetiapine16 and a combination of olanzapine and fluoxetine17 are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.
Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.
Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.
Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.
No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:
Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.18
Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.
Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.
Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.20 Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.
Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.
Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.
Approximately 20% of bipolar patients are thought to experience rapid cycling, defined as ≥4 affective episodes/year separated by at least 2 weeks of euthymia between poles or with an immediate switch from one pole to the other.32 The prevalence of ultradian cycling—in which multiple brief affective episodes (usually subsyndromal or mixed) occur each day—is unclear.
Both cycling types probably represent stages in the evolution of bipolar mood disorders rather than distinct diagnoses. In many cases, mood cycling abates after months to years, but morbidity can be high and the wrong treatment may perpetuate mood cycling.
Complex mood cycling rarely responds to a single treatment, probably because its pathophysiology is complex. The need for polypharmacy may create the impression of treatment failure, but no one would expect a single medication to be sufficient for other complex illnesses such as cancer or AIDS.
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.
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.
Combine mood stabilizers. After optimizing the dose of a single mood stabilizer, add a second one from a different class. In an open trial, adding oxcarbazepine, up to 2,400 mg/d, helped approximately one-third of 20 patients with refractory mood cycling.10 Lithium is generally considered less effective than anticonvulsants in rapid cycling, but at least one study showed it was equivalent to carbamazepine for this problem.35 Lithium combined with other mood stabilizers may be more effective than lithium monotherapy in refractory bipolar states.
Other options to consider in combination with mood stabilizers:
- an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
- clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states36 (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
- nimodipine, which has empiric support for complex mood cycling37 and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
- supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens34 (but risks of inducing hyperthyroidism make this intervention third-line).
Related resources
- Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
- Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
- Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
- Bupropion • Wellbutrin
- Carbamazepine • Tegretol
- Clonazepam • Klonopin
- Clozapine • Clozaril
- Fluoxetine • Prozac
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Levetiracetam • Keppra
- Lithium • Lithobid, others
- Lorazepam • Ativan
- Memantine • Namenda
- Methylphenidate • Concerta, Ritalin, others
- Modafinil • Provigil
- Nimodipine • Nimotop
- Olanzapine/fluoxetine • Symbyax
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Pramipexole • Mirapex
- Pregabalin • Lyrica
- Quetiapine • Seroquel
- Riluzole • Rilutek
- Selegiline • Eldepryl
- Topiramate • Topamax
- Tranylcypromine • Parnate
- Valproate • Depakene, Depakote
- Venlafaxine • Effexor
- Verapamil • Calan, Isoptin, others
- Zonisamide • Zonegran
Dr. Mostert reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.
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.
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.
Mania
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.
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.
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.
- 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 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
In many cases, an antidepressant seems to help at first and then induces a recurrence of depression, often mixed with dysphoric hypomanic symptoms. The recurrent episode improves when the clinician increases the antidepressant dose or changes to another antidepressant, only to be followed by another recurrence that may be interpreted as an incomplete antidepressant response.
Antipsychotics. Quetiapine16 and a combination of olanzapine and fluoxetine17 are approved for treating bipolar depression. The studies supporting this indication lasted only 8 weeks, however, and excluded patients with the kinds of complicated and comorbid mood disorders commonly seen in clinical practice.
Many patients dropped out before the studies were completed, and “screen fails” (patients with the diagnosis who were not enrolled in the study) were not reported. In addition, “remitted” patients remained symptomatic.
Therefore, FDA approval of this indication does not guarantee these medications’ long-term efficacy or safety for bipolar depression or that they are useful in patients with complex forms of bipolar depression.
Recommended approach. Treatment resistance of bipolar depression to multiple mood stabilizers—with or without an antidepressant—or to an antipsychotic may manifest as lack of response, partial response, or initial good response followed by relapse or recurrence. Sometimes depression improves but irritability or mood lability worsen.
No reliable controlled studies have addressed complex refractory bipolar depression, but clinical experience suggests 1 approach for all of these responses:
Reconsider possible hypothyroidism. A low-normal T4—especially if decreased over time—and a mid-range or high-normal TSH—especially if increased—may indicate that subclinical hypothyroidism is inhibiting a response to mood stabilizers and antidepressants.18
Stop the antidepressant. If your patient is taking an antidepressant, it may be ineffective, creating mixed dysphoric hypomania, and/or driving another recurrence of depression. This is especially likely if the patient shows an initial prompt antidepressant response, but depression returns with irritability, insomnia, restlessness, or other subtle symptoms of dysphoric hypomania.
Withdraw the antidepressant gradually; for example, you might reduce the dose by 10% every few weeks so that the agent is discontinued across several months. Discontinuing an antidepressant too rapidly—even if it does not seem to be having any effect—can cause rebound depression that creates the mistaken impression that the antidepressant is needed.
Combine mood stabilizers. If a single mood stabilizer does not at least eliminate mood lability and other symptoms of activation, add a second agent. The combination of lithium and carbamazepine helps some depressed patients.20 Patients with considerable mood instability or psychotic symptoms may benefit from an adjunct antipsychotic.
Introduce mood stabilizers gradually. These medications may work more rapidly against mixed manic symptoms than they do against depression, especially when the dose is raised too quickly. The result is rapid control of irritability, hyperactivity, agitation, and related symptoms but an apparent increase in depression as mixed elements of elevated mood and energy are filtered out.
Add an antidepressant? If gradual adjustment of mood stabilizers eliminates mixed symptoms and mood fluctuations but the patient is still depressed, cautiously add an antidepressant. Antidepressants may be less likely to destabilize mood after all mixed elements have been treated completely.
Approximately 20% of bipolar patients are thought to experience rapid cycling, defined as ≥4 affective episodes/year separated by at least 2 weeks of euthymia between poles or with an immediate switch from one pole to the other.32 The prevalence of ultradian cycling—in which multiple brief affective episodes (usually subsyndromal or mixed) occur each day—is unclear.
Both cycling types probably represent stages in the evolution of bipolar mood disorders rather than distinct diagnoses. In many cases, mood cycling abates after months to years, but morbidity can be high and the wrong treatment may perpetuate mood cycling.
Complex mood cycling rarely responds to a single treatment, probably because its pathophysiology is complex. The need for polypharmacy may create the impression of treatment failure, but no one would expect a single medication to be sufficient for other complex illnesses such as cancer or AIDS.
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.
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.
Combine mood stabilizers. After optimizing the dose of a single mood stabilizer, add a second one from a different class. In an open trial, adding oxcarbazepine, up to 2,400 mg/d, helped approximately one-third of 20 patients with refractory mood cycling.10 Lithium is generally considered less effective than anticonvulsants in rapid cycling, but at least one study showed it was equivalent to carbamazepine for this problem.35 Lithium combined with other mood stabilizers may be more effective than lithium monotherapy in refractory bipolar states.
Other options to consider in combination with mood stabilizers:
- an antipsychotic, especially in the presence of psychotic symptoms, when mixed symptoms are present
- clozapine, which can be a highly effective adjunct for refractory mood cycling and mixed states36 (but is a later adjunct because of required monitoring, common adverse effects, and risk of interactions with carbamazepine and benzodiazepines)
- nimodipine, which has empiric support for complex mood cycling37 and is well-tolerated with fewer interactions than other mood stabilizers (but cost and need for frequent dosing make it a second-line adjunct)
- supraphysiologic doses of thyroxine (≤0.4 mg/d, with T4 levels in the hyperthyroid range), which can improve response to mood-stabilizing regimens34 (but risks of inducing hyperthyroidism make this intervention third-line).
Related resources
- Dubovsky SL. Clinical guide to psychotropic medications. New York: WW Norton; 2005.
- Dubovsky SL. Treatment of bipolar depression. Psychiatr Clin North Am 2005;28:349-70.
- Phillip Long, MD. Internet Mental Health. Online psychiatric diagnosis for the two-thirds of individuals with mental illness who do not seek treatment. www.mentalhealth.com/dis/p20-md02.html.
- Bupropion • Wellbutrin
- Carbamazepine • Tegretol
- Clonazepam • Klonopin
- Clozapine • Clozaril
- Fluoxetine • Prozac
- Gabapentin • Neurontin
- Lamotrigine • Lamictal
- Levetiracetam • Keppra
- Lithium • Lithobid, others
- Lorazepam • Ativan
- Memantine • Namenda
- Methylphenidate • Concerta, Ritalin, others
- Modafinil • Provigil
- Nimodipine • Nimotop
- Olanzapine/fluoxetine • Symbyax
- Oxcarbazepine • Trileptal
- Paroxetine • Paxil
- Pramipexole • Mirapex
- Pregabalin • Lyrica
- Quetiapine • Seroquel
- Riluzole • Rilutek
- Selegiline • Eldepryl
- Topiramate • Topamax
- Tranylcypromine • Parnate
- Valproate • Depakene, Depakote
- Venlafaxine • Effexor
- Verapamil • Calan, Isoptin, others
- Zonisamide • Zonegran
Dr. Mostert reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Dubovsky receives research/grant support from Eli Lilly and Company, Organon, Pfizer, UCB Pharma, anhd Forest Laboratories. He is a consultant to Oganon and Biovail Pharmaceuticals.
1. Judd JL, Akiskal HS, Schettler PJ, et al. A prospective investigation of the natural history of the long-term weekly symptomatic status of bipolar II disorder. Arch Gen Psychiatry 2003;61:261-9.
2. Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEPBD). Am J Psychiatry 2006;163:217-24.
3. Altschuler LL, Post RM, Leverich GS. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J Psychiatry 1995;152:1130-8.
4. Osterberg L, Blaschke T. Drug therapy: adherence to medication. N Engl J Med 2005;353:487-97.
5. Kusalic M. Grade II and grade III hypothyroidism in rapid cycling bipolar patients. Biol Psychiatry 1992;25:177-81.
6. Franks RD, Dubovsky SL, Lifshitz M, et al. Long-term lithium carbonate therapy causes hyperparathyroidism. Arch Gen Psychiatry 1982;39:1074-7.
7. Allen MH, Hirschfeld RMA, Wozniak PJ, et al. Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania. Am J Psychiatry 2006;163:272-5.
8. Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially responsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.
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.
11. Calabrese JR, Kimmel SE, Woyshville MJ, et al. Clozapine for treatment-refractory mania. Am J Psychiatry 1996;153:759-64.
12. Mukherjee S, Sackeim HA, Schnur DB. Electroconvulsive therapy of acute manic episodes: a review of 50 years’ experience. Am J Psychiatry 1994;151:169-76.
13. Michael N, Erfurth A. Treatment of bipolar mania with right prefrontal rapid transcranial magnetic stimulation. J Affect Disord 2004;78:253-7.
14. Baldessarini RJ, Leahy L, Arcona S, et al. Patterns of psychotropic drug prescription for U.S. patients with diagnoses of bipolar disorders. Psychiatr Serv 2007;58:85-91.
15. Sachs GS, Nierenberg AA, Calabrese JR, et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med 2007;356:1711-22.
16. Cookson J, Keck PE, Jr, Ketter TA, Macfadden W. Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study. Int Clin Psychopharmacol 2007;22(2):93-100.
17. Tohen M, Vieta E, Calabrese JR, et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I depression. Arch Gen Psychiatry 2003;60:1079-88.
18. Cole DP, Thase ME, Mallinger AG, et al. Slower treatment response in bipolar depression predicted by lower pretreatment thyroid function. Am J Psychiatry 2002;159:116-21.
19. Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet 2007;369:935-45.
20. Kishimoto A. The treatment of affective disorder with carbamazepine: prophylactic synergism of lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:483-93.
21. McElroy SL, Zarate CA, Cookson J, et al. A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. J Clin Psychiatry 2004;65:204-10.
22. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64:419-26.
23. Ketter TA, Post RM, Parekh PI, Worthington K. Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. J Clin Psychiatry 1995;56:471-5.
24. Himmelhoch JM, Thase ME, Mallinger AG, Houck PR. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991;148:910-6.
25. Zarate CAJ, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004;56:54-60.
26. Lam JY, Freeman MK, Cates ME. Modafinil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants. Ann Pharmacother 2007;41:1005-12.
27. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007;164:1242-9.
28. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry 2005;66:195-8.
29. Post RM, Altshuler LL, Frye MA, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry 2005;66:370-4.
30. Zarate CAJ, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64.
31. Zarate CAJ, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005;57:430-2.
32. Nahas Z, Kozel FA, Li X, et al. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003;5:40-7.
33. Schneck CD. Treatment of rapid-cycling bipolar disorder. J Clin Psychiatry 2006;67(suppl 11):22-7.
34. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder, I: Association with grade I hypothyroidism. Arch Gen Psychiatry 1990;47:427-32.
35. Okuma T, Yamashita I, Takahashi R, et al. Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry 1990;23:143-50.
36. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 1991;11:396-7.
37. Goodnick PJ. Nimodipine treatment of rapid cycling bipolar disorder. J Clin Psychiatry 1995;56:330.-
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19. Benazzi F. Bipolar disorder—focus on bipolar II disorder and mixed depression. Lancet 2007;369:935-45.
20. Kishimoto A. The treatment of affective disorder with carbamazepine: prophylactic synergism of lithium and carbamazepine combination. Prog Neuropsychopharmacol Biol Psychiatry 1992;16:483-93.
21. McElroy SL, Zarate CA, Cookson J, et al. A 52-week, open-label continuation study of lamotrigine in the treatment of bipolar depression. J Clin Psychiatry 2004;65:204-10.
22. Miklowitz DJ, Otto MW, Frank E, et al. Psychosocial treatments for bipolar depression: a 1-year randomized trial from the Systematic Treatment Enhancement Program. Arch Gen Psychiatry 2007;64:419-26.
23. Ketter TA, Post RM, Parekh PI, Worthington K. Addition of monoamine oxidase inhibitors to carbamazepine: preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. J Clin Psychiatry 1995;56:471-5.
24. Himmelhoch JM, Thase ME, Mallinger AG, Houck PR. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry 1991;148:910-6.
25. Zarate CAJ, Payne JL, Singh J, et al. Pramipexole for bipolar II depression: a placebo-controlled proof of concept study. Biol Psychiatry 2004;56:54-60.
26. Lam JY, Freeman MK, Cates ME. Modafinil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants. Ann Pharmacother 2007;41:1005-12.
27. Frye MA, Grunze H, Suppes T, et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry 2007;164:1242-9.
28. Anand A, Bukhari L, Jennings SA, et al. A preliminary open-label study of zonisamide treatment for bipolar depression in 10 patients. J Clin Psychiatry 2005;66:195-8.
29. Post RM, Altshuler LL, Frye MA, et al. Preliminary observations on the effectiveness of levetiracetam in the open adjunctive treatment of refractory bipolar disorder. J Clin Psychiatry 2005;66:370-4.
30. Zarate CAJ, Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006;63:856-64.
31. Zarate CAJ, Quiroz JA, Singh JB, et al. An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression. Biol Psychiatry 2005;57:430-2.
32. Nahas Z, Kozel FA, Li X, et al. Left prefrontal transcranial magnetic stimulation (TMS) treatment of depression in bipolar affective disorder: a pilot study of acute safety and efficacy. Bipolar Disord 2003;5:40-7.
33. Schneck CD. Treatment of rapid-cycling bipolar disorder. J Clin Psychiatry 2006;67(suppl 11):22-7.
34. Bauer MS, Whybrow PC, Winokur A. Rapid cycling bipolar affective disorder, I: Association with grade I hypothyroidism. Arch Gen Psychiatry 1990;47:427-32.
35. Okuma T, Yamashita I, Takahashi R, et al. Comparison of the antimanic efficacy of carbamazepine and lithium carbonate by double-blind controlled study. Pharmacopsychiatry 1990;23:143-50.
36. Calabrese JR, Meltzer HY, Markovitz PJ. Clozapine prophylaxis in rapid cycling bipolar disorder. J Clin Psychopharmacol 1991;11:396-7.
37. Goodnick PJ. Nimodipine treatment of rapid cycling bipolar disorder. J Clin Psychiatry 1995;56:330.-