The STAR*D study: Treating depression in the real world
ABSTRACTThe Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression. Although the study found no clear-cut "winner," it does provide guidance on how to start therapy and how to proceed if initial treatment fails.
KEY POINTS
- Remission (ie, complete relief from a depressive episode) rather than response (merely substantial improvement) should be the goal of treatment, as it is associated with a better prognosis and better function.
- Should the first treatment fail, either switching treat mentor augmenting the current treatment is reasonable.
- For most patients, remission will require repeated trials of sufficiently sustained, vigorously dosed antidepressant medication. Physicians should give maximal but tolerable doses for at least 8 weeks before deciding that an intervention has failed.
- After two well-delivered medication trials, the likelihood of remission substantially decreases. Such patients likely require more complicated regimens. Given the thin existing database, these patients are best referred to a psychiatrist for more complex treatments.
- With persistent and vigorous treatment, most patients will enter remission: about 33% after one step, 50% after two steps, 60% after three steps, and 70% after four steps (assuming patients stay in treatment).
LEVEL 1: WHAT CAN WE EXPECT FROM INITIAL TREATMENT?
At level 1, all the patients received citalopram. The mean dose was 40.6 ± 16.6 mg/day in the primary care clinics and 42.5 ± 16.8 mg/day in the psychiatric clinics, which are adequate, middle-range doses and higher than the average US dose.29
Approximately 30% of patients achieved remission: 27% as measured on the HAM-D17 and 33% on the QIDS-SR16. The response rate (on the QIDS-SR16) was 47%. There were no differences between primary and psychiatric care settings in remission or response rates.
Patients were more likely to achieve remission if they were white, female, employed, more educated, or wealthier. Longer current episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were each associated with lower remission rates.
What is an adequate trial?
Longer times than expected were needed to reach response or remission. The average duration required to achieve remission was almost 7 weeks (44 days in primary care; 49 days in psychiatric care). Further, approximately one-third of those who ultimately responded and half of those who entered remission did so after 6 weeks.30 Forty percent of those who entered remission required 8 or more weeks to do so.
These results suggest that longer treatment durations and more vigorous medication dosing than generally used are needed to achieve optimal remission rates. It is imprudent to stop a treatment that the patient is tolerating in a robust dose if the patient reports only partial benefit by 6 weeks; indeed, raising the dose, if tolerated, may help a substantial number of patients respond by 12 or 14 weeks. Instruments to monitor depression severity (eg, self-report measures) can be useful. At least 8 weeks with at least moderately vigorous dosing is recommended.
LEVEL 2: IF THE FIRST TREATMENT FAILS
When switching to a new drug, does it matter which one?
No.
In level 2, if patients had not achieved remission on citalopram alone, they had the choice of switching: stopping citalopram and being randomized to receive either sertraline (Zoloft, another SSRI), venlafaxine extended-release (XR) (Effexor XR, a serotonin and norepinephrine reuptake inhibitor), or bupropion sustained-release (SR) (Wellbutrin SR, a norepinephrine and dopamine reuptake inhibitor). At the last visit the mean daily doses were bupropion SR 282.7 mg/day, sertraline 135.5 mg/day, and venlafaxine-XR 193.6 mg/day.
The remission rate was approximately one-fourth with all three drugs31:
- With bupropion SR—21.3% by HAM-D17, 25.5% by QIDS-SR16
- With sertraline—17.6% by HAM-D17, 26.6% by QIDS-SR16
- With venlafaxine-XR—24.8% by HAM-D17, 25.0% by QIDS-SR16. The remission rates were neither statistically nor clinically different by either measure.
Though the types of side effects related to specific medications may have varied, the overall side-effect burden and the rate of serious adverse events did not differ significantly.
When adding a new drug, does it matter which one?
Again, no.
Instead of switching, patients in level 2 could choose to stay on citalopram and be randomized to add either bupropion SR or buspirone (BuSpar) to the regimen (augmentation). The mean daily doses at the end of level 2 were bupropion SR 267.5 mg and buspirone 40.9 mg.
Rates of remission32:
- With bupropion SR—29.7% on the HAMD-D17, 39.0% on the QIDS-SR16
- With buspirone—30.1% on the HAM-D17, 32.9% on the QIDS-SR16.
However, the QIDS-SR16 scores declined significantly more with bupropion SR than with buspirone (25.3% vs 17.1%, P < .04). The mean total QIDS-SR16 score at the last visit was lower with bupropion SR (8.0) than with buspirone (9.1, P < .02), and augmentation with bupropion SR was better tolerated (the dropout rate due to intolerance was 12.5% with bupropion-SR vs 20.6% with buspirone 20.6%; P < .009).
Can we directly compare the benefits of switching vs augmenting?
No.
Patients could choose whether to switch from citalopram to another drug or to add another drug at the second treatment level.33 Consequently, we could not ensure that the patient groups were equivalent at the point of randomization at the beginning of level 2, and, indeed, they were not.
Those who benefitted more from citalopram treatment and who better tolerated it preferred augmentation, while those who benefitted little or who could not tolerate it preferred to switch. Consequently, those in the augmentation group at level 2 were somewhat less depressed than those who switched. Whether augmentation is better even if the initial treatment is minimally effective could not be evaluated in STAR*D.
What about cognitive therapy?
There was no difference between cognitive therapy (either as a switch or as augmentation) and medication (as a switch or as augmentation).34 Adding another drug was more rapidly effective than adding cognitive therapy. Switching to cognitive therapy was better tolerated than switching to a different antidepressant.
Of note, fewer patients accepted cognitive therapy as a randomization option than we expected, so the sample sizes were small. Possible reasons were that all patients had to receive a medication at study entry (which may have biased selection towards those preferring medication), and cognitive therapy entailed additional copayments and visiting still another provider at another site.
After two levels of treatment, how many patients reach remission?
About 30% of patients in level 1 achieved remission, and of those progressing to level 2, another 30% achieved remission. Together, this adds up to about 50% of patients achieving remission if they remained in treatment (30% in level 1 plus 30% of the roughly 70% remaining in level 2).
