Bipolar disorder causes havoc in patients’ lives. Even in the best of circumstances, successful treatment is challenging. Treatment targets constantly shift; patients are frequently nonadherent; and comorbidity is the rule, not the exception. Diagnosis of bipolar disorder is often difficult. Comorbidities need to be identified and addressed if treatment is to be effective.

The importance of an accurate diagnosis

With apologies to Charles Dickens, bipolar disorder is often experienced as the “best of times and the worst of times.” This polarity often causes bipolar disorder to be undiagnosed, overdiagnosed, or misdiagnosed. Bipolar disorder is associated with a significantly elevated risk of suicide. Moreover, bipolar patients often use highly lethal means for suicide.¹ Contributing factors include early age at disease onset, the high number of depressive episodes, comorbid alcohol abuse, a history of antidepressant-induced mania, and traits of hostility and impulsivity.

Bipolar I disorder, with episodes of full-blown mania, is usually easier to diagnose than bipolar II disorder, with episodes of subtler hypomania. Recognizing that the primary mood state may be irritability rather than euphoria increases the likelihood of diagnosis as does the recognition that symptoms often last fewer than the 4 days required for diagnosis by DSM-IV.² Focusing more on overactivity than mood change further improves diagnostic accuracy, and the use of structured questionnaires is helpful.

Given the greater frequency of depression than manic episodes in bipolar disorder, what clues indicate bipolar disorder rather than unipolar depression? The Table lists factors that may help identify unipolar depression.

A moving target needs moving treatment

Effective personalized treatment recognizes bipolar disorder as a biopsychosocial disorder, but mood-stabilizing medications are the backbone of treatment. These medications fall into 3 categories: lithium, antikindling/antiepileptic agents, and second-generation antipsychotics. The mechanisms of actions by which these medications work are numer-ous and include increasing levels of serotonin, γ-aminobutyric acid, and brain-derived neurotrophic factor (BDNF) and decreasing glutamate levels; modifying dopamine pathways; stabilizing neuronal membranes; decreasing sodium channels; decreasing depolarization; decreasing apoptosis; and increasing neural cell growth/arborization.

Double-blind placebo-controlled studies of the medications—lithium, divalproex, carbamazepine, and atypical antipsychotics—used to treat symptoms of acute mania have demonstrated a response rate of approximately 50% to these drugs. Response was defined as a 50% decrease in symptoms using the Young Mania Rating Scale (YMRS) with onset of response within a few days.

An increasingly intriguing aspect of treatment with lithium and atypical antipsychotics involves their effect on BDNF. In a study of 10 manic patients treated with lithium for 28 days, most (87%) showed an increase in BDNF level (ie, from 406 pg/mL to 511 pg/mL).³

TABLE

Factors that suggest bipolar depression rather than unipolar depression

In a typical 3-week study of acute mania, approximately half of the benefit was seen by day 4. A 3-week, double-blind, inpatient study of olanzapine and risperidone in 274 patients with acute mania found that of 117 patients who had a less than 50% decrease in the YMRS score at 1 week, only 39% responded and 19% had symptom remission at end point. Of 40 patients with a less than 25% decrease in the YMRS score at 1 week, only 25% responded and only 5% had symptom remission at 3 weeks. Of 157 patients who had at least a 50% decrease in the YMRS score at week 1, 84% responded and 64% had symptom remission at 3 weeks.⁴ Clinically, a medication change should be considered for patients who do not demonstrate substantial benefit by week 1.

A meta-analysis comprising 16,000 patients who had acute mania found that the most effective agents were haloperidol, risperidone, and olanzapine. The least effective were gabapentin, lamotrigine, and topiramate.⁵

A combination of medications—typically lithium or an antiepileptic with an atypical antipsychotic—is often necessary to successfully treat acute mania. A meta-analysis found the response rate increased from 42% to 62% when an antipsychotic was added.⁶

Bipolar depression has proved to be more resistant to medication treatment than mania. The same medications are used, with lamotrigine for maintenance treatment. The FDA has approved Seroquel, Seroquel XR, and Symbyax (the combination of olanzapine and fluoxetine), for the acute treatment of bipolar depression. Studies of acute bipolar depression have typically lasted 8 weeks. Approximately half of the benefit oc-curs by week 2, with statistical separation from placebo between weeks 1 and 3.^7-9

The best treatment is prevention

Patients who have bipolar disorder almost always require lifelong maintenance treatment, frequently with 2 medications: one to prevent the upside (ie, hypomania/mania), and another to prevent the downside (ie, depression).

Findings from a registration trial showed that lamotrigine more effectively prevented depressions than lithium but lithium prevented mania/hypomania more effectively than lamotrigine.¹⁰

Another study added placebo or lamotrigine to lithium treatment for 124 patients. The median time to relapse/recurrence was 3.5 months for those taking lithium monotherapy but 10 months for those who received combination treatment.¹¹

The effectiveness of a combination maintenance regimen was also seen in a study of 628 patients with bipolar I disorder treated for 2 years: 65% of those taking lithium or divalproex alone experienced a recurrence compared with 21% who received quetiapine added to lithium or divalproex.¹² However, combination treatment may result in more adverse effects and increased risk of drug-drug interactions.

The best mood stabilizer

The best mood stabilizer for a patient is the one he or she will take. No matter how effective a medication is, it will not relieve symptoms if it is not being taken. The key to effective personalized treatment of bipolar disorder is a good patient-physician connection in which the patient is part of the treatment decision-making process.

Psychotherapy is an integral part of the effective treatment of bipolar disorder, not just an augmentation strategy. Psychotherapies that are helpful include cognitive-behavioral therapy and social rhythm therapy.¹³ Psychotherapy can focus on several areas, such as education, comorbidities, medication adherence, and interpersonal relationships. In addition, therapy can challenge the automatic, distorted, and dysfunctional thoughts and help the patient maintain social rhythms (eg, consistent sleep). The involvement of family members in treatment enhances success.