Antidepressant and Antimanic Medications: Continuation- and Maintenance-Phase Efficacy
Most experts now agree that the majority of patients with a mood disorder will have more than one episode. Recurrence rates for depression are estimated to be at least 50% for patients with one prior MDE and 80%-90% for patients with two prior MDEs. Recurrence rates for bipolar disorder are equally high, although several studies suggest that substantial numbers of patients (up to 50% with a prior single episode of mania) will have only a single episode. These high rates of recurrence and relapse have highlighted the need for consideration of the efficacy of antidepressant and antimanic treatments in continuation and maintenance phases of treatment.
It is generally accepted that patients who show significant improvement during the acute-treatment phase should continue to be given antidepressant drugs for at least 6 months. Drugs that are effective in acute treatment of an MDE have generally been found to be efficacious in continuation treatment. Fortunately, the same appears to be true for these drugs’ efficacy in maintenance treatment. These consistent findings, in the face of the relative safety of the majority of antidepressant drugs, underscore the importance of continuation and maintenance treatment.
Most classes of antidepressants have been studied in continuation treatment, although most of these studies were extensions of acute-treatment studies and the number of patients in many of the studies was small. Imipramine, amitriptyline, desipramine, nortriptyline, maprotiline, lithium, bupropion, phenelzine, fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, trazodone, nefazodone, mirtazapine, reboxetine, and moclobemide have shown efficacy in continuation treatment.
Maintenance treatment studies have taken on considerable importance in light of recent findings of high rates of relapse and recurrence in patients with relatively uncomplicated MDE following continuation treatment. Between 70% and 90% of patients with a successfully treated MDE will experience a recurrence of illness when placebo is substituted for active medication during a 3-year maintenance phase as opposed to only 15%-20% taking full-dose imipramine. In a prospective, 10-year epidemiological follow-up study of young depressed patients, 78% relapsed during the follow-up period.
The most studied medication in the maintenance treatment of an MDE is imipramine. The Pittsburgh Group’s study investigating the long-term effectiveness of maintenance imipramine treatment has, by virtue of its scientific rigor and methodological and statistical excellence, become the model for future maintenance studies. This study and earlier studies by the same group and by Prien et al. have made imipramine the standard with which other drugs will be compared. The studies cited above have demonstrated that the rate of relapse or recurrence during imipramine treatment is between 20% and 30% over a 1- to 3-year period of treatment, whereas the rate with placebo approaches 80% over that same period. The more recent studies indicate that a total dosage of imipramine below the usual therapeutic range (150-300 mg/day) leads to a higher rate of relapse, which suggests that maintenance treatment should employ full antidepressant doses.
The only other TCAs to have been studied in maintenance treatment are the tertiary-amine mixed serotonin/NE reuptake inhibitor amitriptyline and the secondary-amine NE reuptake inhibitor nortriptyline. Several studies have shown amitriptyline to be as effective as imipramine and more effective than placebo in maintenance treatment. These early studies were not as rigorous as the more recent Pittsburgh Group imipramine study (Kupfer et al. 1992) and did not standardize drug dosages or monitor drug plasma levels. These factors probably underlie the higher rate of recurrence (up to 60%) during amitriptyline maintenance treatment in some of these studies.
One study compared the efficacy of nortriptyline with those of placebo and phenelzine in 1-year maintenance treatment for depression in older patients (age 55 years or above). Nortriptyline (n = 13) was no more effective than placebo (n = 12) in this small group of patients, whereas phenelzine (n = 15) was more effective than placebo (n = 11). The rate of relapse was 65% for placebo, 54% for nortriptyline, and 13% for phenelzine. Although the sample size for this study was small, the methods were rigorous (double-blind, prospective design), and careful attention was paid to plasma drug level and symptom assessment. These findings raise important questions about the long-term efficacy of nortriptyline that need to be resolved, given its use in elderly patients.
Another placebo-controlled maintenance treatment study of phenelzine in depressed patients showed a comparably low rate of recurrence for phenelzine maintenance treatment. This study found that 80% of placebo-maintained patients, but only 30% of phenelzine-maintained patients, had a recurrence.
Newer antidepressants are generally being tested for efficacy in the maintenance treatment of MDE. All of the SSRIs have been studied. Fluoxetine, sertraline, and paroxetine all showed a significantly lower rate of relapse than placebo. A large, multicenter maintenance study comparing sertraline and imipramine in the treatment of patients with double depression (i.e., dysthymia and MDE) or chronic MDE demonstrated that both of these drugs are effective in the maintenance treatment of these chronic forms of depression.
Open-label extension studies have been conducted with trazodone, doxepin, bupropion, and maprotiline. These studies suggest that most patients who have responded will continue to respond. Other antidepressants have not been studied in this regard.
In summary, one can infer from the results of the studies that have been conducted to assess the efficacy of antidepressant drugs in the maintenance phase of treatment of MDEs that most medications will be effective. These studies suggest that when maintenance treatment is initiated, full antidepressant doses should be continued. Rates of depressive relapse appear to be higher when antidepressant drugs are discontinued rapidly compared with a slow (3-4 weeks) taper.
The only antimanic medication that has been studied to date for continuation/maintenance-phase treatment is lithium. Trials with valproate have been completed but not yet published. Lithium has been shown to be more effective than placebo and antipsychotic drugs in the prevention of manic episodes. The same factors that are associated with lithium nonresponse in acute treatment (see
Table 39-8) also predict recurrence during maintenance treatment with lithium. Lithium is effective in the prevention of MDEs as well as manic episodes in patients with bipolar disorders. However, it is less effective in the prevention of MDEs than imipramine combined with lithium when the episode that brought the patient into the study (the index episode) was a depressive episode.
Maintenance plasma levels of lithium are related to rates of recurrence. Patients maintained with low plasma lithium levels (0.4-0.6 nmol/L) were more than three times more likely to have manic recurrences than were patients maintained with standard (0.8-1.0 nmol/L) plasma lithium levels. Interestingly, although standard lithium levels led to fewer manic recurrences, patients receiving these doses had significantly more side effects and dropped out of treatment or were noncompliant more often than patients who were maintained on low plasma levels, resulting in comparable effectiveness.
Antidepressant and Antimanic Medications
Combined Medication and Psychotherapy
Treatment-Resistant Mood Disorders
Treatment of Mood Disorders in the Medically Ill Patient
Strategies and Tactics in the Treatment of Depression
Revision date: July 8, 2011
Last revised: by Jorge P. Ribeiro, MD