Treatment recommendations. The key to using mood stabilizers is to achieve the optimum response—assuming good tolerability—before switching to another agent. Adjust medication dosages one at a time to allow adequate response and assessment.
When switching medications, use an overlap-and-taper strategy, assuming there is no medical necessity to stop a drug abruptly. Add the new medication, then gradually taper the one that is being discontinued. Monitor serum levels.
Discontinue antidepressants when appropriate in patients with hypomania/mania or rapid cycling, and continually evaluate suicide and homicide potential of patients in mixed or depressive states.
Stage 1: Monotherapy. First medication choices are lithium, divalproex, or olanzapine. For mixed or dysphoric mania, the algorithm recommends divalproex (preferred over valproic acid because of tolerability and side effects) or olanzapine.6 Data suggest dysphoric manic patients are less likely to respond to lithium.7 A Consensus Panel minority expressed concern about using olanzapine as first-line monotherapy for acute mania because of limited data on the drug’s long-term safety. Patients with partial response or residual symptoms may move to stage 2 or switch to other medication options within stage 1.
Patients with psychotic mania move directly to stage 4 for a broader range of combination therapy.
Stage 2: Combination therapy. Combination therapy has become the standard of care in treating most patients with bipolar disorder. The algorithm recommends using two agents:
- lithium or an anticonvulsant plus another anticonvulsant ([Li or AC]+AC)
- or lithium or an anticonvulsant plus an atypical antipsychotic ([Li or AC]+AAP).8
Recommended agents include lithium, divalproex, oxcarbazepine, olanzapine, or risperidone. The experts recommended oxcarbazepine as first choice because it is better tolerated and interacts with fewer drugs than carbamazepine and does not require serum level monitoring.9
A Consensus Panel minority expressed concern that few studies had examined using oxcarbazepine in bipolar disorder. Carbamazepine was also considered an option.
Stages 3 and 4: Other two-drug combinations. Other two-drug combinations are tried at these stages, drawing from the same pool of medication classes described in stage 2.
Stage 4 broadens the choice of atypical antipsychotic by adding quetiapine10 and ziprasidone11 to the recommended stage-2 agents olanzapine and risperidone. When the 2000 algorithm was developed, limited data were available on using some newer atypicals in patients with bipolar mania. Based on recent, high-quality studies of mono- and combination therapy—including quetiapine,10 ziprasidone,11 risperidone,12,13 and aripiprazole14 —the 2004 algorithm update panel will likely recommend using atypicals earlier, including at stage 1.
Algorithm 1 Treating mania/hypomania in patients with bipolar I disorder
Stage 5: Triple-drug combination. Lithium, an anticonvulsant (divalproex or oxcarbazepine), and an atypical antipsychotic (olanzapine, risperidone, quetiapine, or ziprasidone) is a recommended triple-drug combination. In the 2004 update, the choices will likely expand to include all the newer atypicals and will list carbamazepine as an option.
Stage 6: ECT or clozapine. For patients with inadequate response to triple-drug combinations, the algorithm recommends adding electroconvulsive therapy (ECT) or clozapine.
ECT15 is recommended three times a week until the patient achieves remission of manic symptoms or fails to achieve a sustained response over three to six treatment cycles. Treatment resistance is declared if no response is seen after 6 to 10 treatment cycles.
Clozapine’s16 recommendation at this stage is consistent with its use in patients who fail to respond to other atypical antipsychotics. Blood monitoring for agranulocytosis is required; other adverse effects include an increased risk of seizures, myocarditis, and orthostatic hypotension.
Stage 7: Other. Treatment options such as topiramate17,18 and lamotrigine19 are recommended at this stage. These recommendations also will be reviewed and likely revised.
Treating bipolar depression
The TMAP algorithm for treating depression in bipolar disorder (Algorithm 2) assumes that anti-depressants will be used only with optimum mood-stabilizer levels because of the risk of inducing manic symptoms. The bipolar depression algorithm is always used with the primary algorithm for mania/hypomania.
The patient’s clinical presentation guides medication selection. For the “pure” bipolar I patient with a major depressive episode but little mood lability or hypomania, starting an antide-pressant is a clear decision. On the other hand, patients with predominant depressive symptoms plus dysphoric hypomania, mood lability, and irritability need a balance of mood-stabilizing drugs and antidepressants.
Stage 1: Mood stabilizer. Initiate a mood stabilizer and optimize the dosage. Choices are the same mood stabilizers listed in the hypomania/mania treatment algorithm.
Stage 2: Antidepressant. Adding an antidepressant implies that depressive symptoms are severe enough to change treatment. Antidepressant options include a selective serotonin reuptake inhibitor (SSRI), sustained-release bupropion, or lamotrigine.20
Using SSRIs is supported by widespread clinical experience and offers the convenience of once-daily dosing. Recommended SSRIs include fluoxetine, paroxetine, fluvoxamine, sertraline, and citalopram. The SSRI escitalopram was introduced after the 2000 algorithms were published; evidence for using it and other newer medications will be reviewed for the 2004 update.