Augmentation

ACTION STATEMENT

Augmentation with medication may be considered for patients who have had a partial response to antidepressant monotherapy at a therapeutic dose after at least 6 weeks. The augmenting medication selected should be based on the patient’s current medications (including antidepressants), co-morbid conditions, and adverse effect profile.

BACKGROUND

Augmentation is useful for patients who have demonstrated a partial response tolerance to an antidepressant and wish to remain on that agent instead of switching to a different agent. Augmentation can be introduced at any place in therapy, after a partial response to an initial agent or a partial response after several trials of monotherapy. Clinicians may want to consider augmentation prior to trials with a tricyclic antidepressant or monoamine oxidase inhibitor.

RECOMMENDATIONS

1. Augmentation can be introduced at any point in therapy, provided the patient has demonstrated a partial response to an existing antidepressant

2. Bupropion SR and anxiolytic buspirone are the preferred initial augmentation strategies given their ease of use and lower risk of toxicity.

3. The atypical antipsychotics, with the exception of clozapine, can be considered as an alternative augmentation strategy, but should only be considered when other more established augmentation agents have either failed to result in remission or are contraindicated.

RATIONALE

Bupropion SR and buspirone are equally effective at achieving remission when used to augment first-line antidepressant treatment (SSRIs). Bupropion SR and buspirone are recommended as initial choices for augmentation since their efficacy has been demonstrated in at least one randomized clinical trial and their safety and tolerability profiles are more favorable than lithium.

a. Bupropion SR: Initial dose 100 mg twice a day, increasing after 2 weeks to 150 mg twice daily, and then again in another 2 weeks, if necessary, to 200 mg twice daily: Maximum dose: 400 mg/day.

b. Buspirone: Initial dose 7.5 mg twice a day, increasing to 15 mg twice a day after 1 week, then increasing the dose by 15 mg/day every 2 to 3 additional weeks; Maximum dose: 60 mg/day.

Dose adjustments may be necessary based on age, renal or hepatic function, or concurrent drug therapy.

Lithium and triiodothyronine (T3) have been studied as augmentation strategies for first-line and tricyclic antidepressants. Lithium is the best-studied augmentation strategy with more than 10 controlled clinical trials. Response has been more consistent when combined with a TCA or MAOI, than an SSRI. Triiodothyronine is preferred to thyroxine (T4) due to its quicker onset and offset of action.

a. Lithium: Initial dose: 300 milligrams or 450 milligrams as a single daily dose or in divided doses. The dose can be increased by 50 to 100 percent every 1 to 2 weeks depending on the patient’s tolerability and renal function. Target lithium plasma concentration is >0.5 and <1 milliequivalents/L; Maximum dose 900milligrams/day.

b. T3: Initial dose: 25 micrograms daily, increase to 50 micrograms daily after 1-week. Maximum dose: 50 micrograms per day.

Dose adjustments may be necessary based on age, renal or hepatic function, or concurrent drug therapy.

All the atypical antipsychotics, with the exception of clozapine, have been reported to improve response or remission rate when used to augment an antidepressant.

EVIDENCE STATEMENTS

o Augmentation can be introduced at any point in therapy, provided the patient has demonstrated a partial response to an existing antidepressant.

o Augmentation was a treatment option in Steps 2, 3 and 4 of the STAR*D trial. Augmenting citalopram with bupropion SR or buspirone resulted in remission rates of 39 percent and 32.9 percent after means of 5.7 and 4.8 weeks, respectively. Higher percentages of subjects remitted with augmentation than by switching to a different agent, although this may reflect differences in the rates of partial response and tolerability to citalopram as monotherapy in Step 1. Augmentation of bupropion, sertraline, citalopram or venlafaxine with lithium or T3 was an option in Steps 3 and 4. Remission rates were 14.5 percent and 25.7 percent for lithium and T3, respectively (p>.05); the mean time to remission was 5.3 weeks for both groups. Lithium was not as well tolerated as T3. (Rush et al., 2006b)

o A systematic review and meta-analysis of 10 randomized, double-blind, placebo-controlled clinical trials assessed the efficacy of atypical antipsychotics (olanzapine, risperidone, quetiapine, or ziprasidone) as augmentation agents to antidepressants in patients with treatment resistant depression. The pooled remission and response rates favored the augmentation of atypical antipsychotics vs. placebo, 47.4 percent vs. 22.3 percent and 57.2 percent vs. 35.4percent, with a pooled risk ratios of 1.75 (95%CI: 1.36 to 2.24, p<.0001) and 1.35 (95% CI: 1.13 to 1.63, p=.001), respectively. (Papakostas et al., 2007)

o In one retrospective chart review of 76 trials, reported augmentation with olanzapine, quetiapine, risperidone, or ziprasidone in 49 patients resulted in an overall improvement in CGI-I ratings in 65 percent of patients (32/49). Individual response rates varied by agent: olanzapine 57 percent (21/37), risperidone 50 percent (7/14), quetiapine 33percent (6/18), and ziprasidone 10 percent (1/10). Lack of response to one atypical antipsychotic medication did not predict response to another agent. (Barbee et al., 2004)

o Combination of olanzapine and fluoxetine in patients with treatment resistant major depressive disorder was not shown to provide a superior response to either drug alone or to nortriptyline after 8 weeks in a double-blind trial that randomly assigned 500 patients who had not responded to separate trials with an SSRI and nortriptyline (Shelton et al., 2005).

o Augmentation with aripiprazole was found to result in higher remission and response rates compared to placebo in an 8-week, randomized, double blind trial of 362 patients who had not had an adequate response to an antidepressant. Remission and response rates both favored

aripiprazole over placebo (18.8% and 8.7%, p=.006 and 26% and15.7%, p=.011). The number needed to treat was 10.

o Results of open-label augmentation with aripiprazole have been reported for 15 patients with major depressive disorder who had either partial response or no response to an SSRI, bupropion or venlafaxine. Nine patients achieved remission by the end of their second week taking aripiprazole and all 8 patients completing the 8-week trial achieved remission. The most common reason for discontinuing treatment was akathesia in 3 patients (Simon et al., 2005).

EVIDENCE TABLE

Evidence Source QE Overall

Quality SR 1 Augmentation can be introduced at

any time during treatment, provided the patient has

demonstrated a partial response to an existing antidepressant.

Rush et al., 2006b

Barbee et al., 2004 I Fair B

2 Consider atypical antipsychotics after other augmenting agents have failed or are contraindicated

Papakostas et al., 2007

Berman et al., 2007 I Fair B