The Impact of Antidepressant Discontinuation on Relapse, Remission, and Mood Episode Cycling in Bipolar Disorder

Presented at the American Psychiatric Association 2004 Annual Meeting

The appropriate administration of antidepressants in patients with bipolar disorder is a challenging clinical problem. Antidepressants can, even in the presence of the administration of an adequate dose of a mood stabilizer, induce mania and cycling. Since there are now several clinical alternatives to antidepressant use in patients with cycling mood, these questions are of great clinical relevance in this difficult-to-treat population. Three studies were presented at the American Psychiatric Association 2004 Annual Meeting that attempted to address these questions.

The current studies were part of a large STEP-BD (Systemic Treatment Enhancement Program for Bipolar Disorder) study being conducted at numerous study sites nationally.[1] In a study by Pardo and colleagues,[2] 33 patients who had responded to a mood stabilizer and adjunctive antidepressant were included. Subjects were openly randomized to either discontinue the antidepressant (short-term [ST] group) or continue on the medication (long-term [LT] group). Patients were rated using the Life Chart Methodology as well as the Clinical Monitoring Form, and they were followed for a period of 1 year. The antidepressants utilized included selective serotonin reuptake inhibitors (64%), bupropion (Wellbutrin XL) (21%), venlafaxine (Effexor) (7%), and methylphenidate (Ritalin) (7%). The mood stabilizers included lithium (Eskalith) (55%), divalproex (Depakote) (12%), lamotrigine (24%), and others (70%).

The findings were as follows:

1. Subjects were rated as euthymic 58.6% of the time, depressed 30.3% of the time, and manic 4.88% of the time.
2. The time in remission was similar in the ST group (74.2%) compared with the LT group (67.3%). Remission was defined as <!--= 2 DSM-IV mood criteria for 2 or more months.
3. The number of mood episodes was similar in the ST group (1.0 ± 1.6) compared with the LT group (1.1 ± 1.3).
4. A history of rapid cycling, substance abuse, and psychotic features were associated with poorer outcome.
5. Females remained well longer than males.

Although clinical courses vary widely in this disorder, many patients with bipolar disorder suffer more frequently from depression than from manic episodes. This was true in these studies; the patients were rated as being in a depressed mood 30.3% of the time and in a manic state only 4.88% of the time. Serious adverse events such as suicide are more common during depressive episodes. Therefore, rigorous treatment of depressive episodes is essential to optimally treat the patient with bipolar disorder. There have been numerous reports and studies concerning the risk of antidepressant use in bipolar disorder. In work by Altshuler and colleagues,^[3] it was estimated that 35% of patients with treatment-refractory bipolar disorder experienced a manic episode that was rated likely to be antidepressant-induced. Cycle acceleration was thought likely to be associated with antidepressants in 26% of the patients assessed. Forty-six percent of patients who demonstrated antidepressant mania had a prior history of this. This compared with a history of antidepressant mania in only 14% of patients who did not currently show antidepressant cycling.

In a study by Post and associates,^[4] 258 outpatients with bipolar disorder were followed prospectively and rated on the National Institute of Mental Health-Life Chart Method (NIMH-LCM) for a period of 1 year. In the second part of the study, 127 bipolar depressed patients were randomized to receive a 10-week trial of sertraline, bupropion, or venlafaxine as adjunctive treatment to mood stabilizers. Patients who did not respond to this regimen were rerandomized and responders were offered a year of continuation treatment.

The number of days spent depressed among the 258 outpatients was 3 times the rate of manic symptoms. These symptoms persisted even with intensive outpatient treatment provided in the study. During the 10-week antidepressant trial, 18.2% experienced switches into hypomania or mania or exacerbation of manic symptoms. In the 73 patients who were continued on the antidepressants, 35.6% experienced switches or exacerbation of hypomanic or manic symptoms.

Alternative options now available for the treatment of the depressed phase of bipolar disorder include lamotrigine, more aggressive treatment with mood stabilizers, and/or use of adjunctive treatment with atypical agents. The risks vs the benefits of sustained treatment with antidepressants must be weighed to make a rational decision as to continued use of these agents.^[5] Data from a study by Hsu and colleagues^[6] suggest that antidepressant continuation does not lead to increased time in remission in bipolar disorder, compared with antidepressant discontinuation.

Bipolar Disorder and Comorbid Conditions

The purpose of a study by Simon and colleagues^[7] was to determine to what extent comorbid conditions are linked to the adequate use of mood stabilizers and other pharmacologic interventions. The first 1000 patients enrolled into a large 20-site study on bipolar disorder (STEP-BD) were included in this study. The treatments were rated for adequacy based on predecided criteria for mood stabilizer use as well as treatment of associated specific disorders (eg, attention-deficit/hyperactivity disorder [ADHD], substance abuse, anxiety disorders).

The rates of comorbidity were as follows: current anxiety disorder in 32%; lifetime substance abuse disorder in 48%; current alcohol use in 8%; current ADHD in 6%; current eating disorder in 2%; and past eating disorder in 8%.

With regard to pharmacologic interventions:

1. A total of 7.5% of the sample were not treated with any psychotropic medications.
2. A total of 59% were not on adequate mood stabilizers. The extent of adequate mood stabilizer treatment was not related to comorbid diagnosis or bipolar I or II status.
3. Only 42% of individuals with a current anxiety diagnosis were receiving adequate treatment for this disorder.
4. The presence of comorbid conditions was only minimally associated with the appropriateness or extent of psychopharmacologic intervention.