Patients may stop taking their medications because the adverse effects become intolerable; they may miss what they perceive as their more satisfying and productive hypomania; and they might believe that a period without symptoms means that they are cured and no longer need medications. One study of 3640 patients with bipolar disorder who made 48,000 physician visits found that 24% of patients were nonadherent (defined as missing at least 25% of doses) 20% of the time. Factors associated with nonadherence included rapid cycling, suicide attempts, earlier onset of illness, anxiety, and alcohol(Drug information on alcohol) abuse.14
Patients who have bipolar II disorder spend far more time depressed than hypomanic. Lithium(Drug information on lithium) appears to be less effective than antikindling agents for rapid cycling as well as for mixed bipolar disorder states.15
Maintenance treatment is necessary for patients with acute mania or acute depression; therefore, choose medications that are more tolerable to the patient to facilitate long-term adherence. Recognize that medications may need to be adjusted or changed—in the acute phase of illness, rapid efficacy is often the priority, while medication adherence is the priority during the maintenance phase.
Other factors to consider when choosing the best medication for a particular patient include:
• A history of treatment response
• A family history of response
• Adverse effects of a particular drug
• Drug interactions
The use of antidepressants in bipolar disorder is controversial because they may induce rapid cycling, especially in patients with episodes of rapid cycling.16 In a study by Altshuler and colleagues,17 patients who had breakthrough depression despite treatment with a mood stabilizer were treated with antidepressants for at least 60 days. Patients who had symptom remission for 6 weeks were followed up for 1 year: 36% of patients who continued antidepressants for longer than 6 months relapsed versus 70% who discontinued antidepressants before 6 months.
A randomized discontinuation study with antidepressants found no statistically significant symptomatic benefit in the long-term treatment of bipolar disorder.18 Trends toward mild benefits, however, were found in patients who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with continuation of modern antidepressants, including SSRIs and SNRIs.
An NIMH study of 159 patients who had breakthrough depression despite receiving a mood stabilizer were treated with sertraline(Drug information on sertraline) (mean dosage, 192 mg/d), bupropion (mean dosage, 286 mg/d), or venlafaxine (mean dosage, 195 mg/d) for 10 weeks with a 1-year follow-up.19 At the end of 1 year, only 16% of the patients had continued remission while more than 55% had switched to mania/hypomania. The worst results were seen with venlafaxine and the best with bupropion.
In a study by Sachs and colleagues,20 patients who had breakthrough depression despite being treated with mood stabilizers were randomized to paroxetine(Drug information on paroxetine) (mean dosage, 30 mg/d), bupropion (mean dosage, 300 mg/d), or placebo. No significant differences on any effectiveness or safety outcome, including remission rates or affective switch frequency, were found.
Overall, these studies indicate that the role of antidepressants is limited and that, in fact, a trial of a mood stabilizer cannot be considered to have failed unless the failure occurs in the absence of an antidepressant. A meta-analysis of 18 studies with 4105 patients found that combination treatment including a mood stabilizer and an antidepressant was not statistically superior to monotherapy.21
When symptoms persist
Establish the context of each appointment by focusing on changes in occupational, social, family, and health status. Evaluate medication regimens, with a focus on effectiveness for carefully chosen target symptoms and adherence to treatment, as well as medication tolerability and patient attitudes. Be alert to the emergence of early symptoms of mood change, and adjust medications if necessary. Remember that treatment modalities often need to change over time.
Mood stabilizers should be optimized with combination therapy for sustained remission. Antidepressants may worsen the disease course, and a true trial of a mood stabilizer can-not occur within the setting of antidepressants. If symptoms persist, ask: Is the patient taking anything that is making symptoms worse, eg, drugs, alcohol, or antidepressants? Is the patient taking the medications? Is treatment adequate? Is another condition (including subclinical hypothyroidism) interfering with treatment? Is psychotherapy being ignored?