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).
IF A SECOND TREATMENT FAILS
If switching again to another drug, does it matter which one?
No.
In level 3, patients could choose to stop the drug they had been taking and be randomized to receive either mirtazapine (Remeron) or nortriptyline (Pamelor).
Switching medications was not as effective as a third step as it was as a second step.35
Remission rates:
- With mirtazapine—12.3% on the HAM-D17, 8.0% on the QIDS-SR16
- With nortriptyline—19.8% on the HAM-D17, 12.4% on the QIDS-SR16.
Response rates were 13.4% with mirtazapine and 16.5% with nortriptyline. Statistically, neither the response nor the remission rates differed by treatment, nor did these two treatments differ in tolerability or side-effect burden.
Does choice of augmentation agent matter: Lithium vs T3?
Similarly, after two failed medication treatments, medication augmentation was less effective than it was at the second step.36 The two augmentation options tested, lithium and T3 thyroid hormone (Cytomel), are commonly considered by psychiatrists but less commonly used by primary care doctors.
Lithium is believed to increase serotonergic function, which may have a synergistic effect on the mechanism of action of antidepressants; a meta-analysis of placebo-controlled studies supports lithium’s effectiveness as adjunctive treatment.37 Its side effects, however, must be closely monitored.38 The primary monitoring concern is the small difference between the therapeutic blood level (0.6–1.2 mEq/L) and potentially toxic blood levels (> 1.5 mEq/L).
Lithium was started at 450 mg/day, and at week 2 it was increased to the recommended dose of 900 mg/day (a dose below the target dose for bipolar disorder). If patients could not tolerate 450 mg/day, the initial dose was 225 mg/day for 1 week before being increased to 450 mg/day, still with the target dose of 900 mg/day. The mean exit dose was 859.9 mg/day, and the median blood level was 0.6 mEq/L.
Thyroid hormone augmentation using T3 is believed to work through both direct and indirect effects on the hypothalamic-pituitary-thyroid axis, which has a strong relationship with depression. The efficacy of T3 augmentation is supported by a meta-analysis of eight studies,39 and T3 is effective whether or not thyroid abnormalities are present.
In STAR*D, T3 was started at 25 μg/day for 1 week, than increased to the recommended dose of 50 μg/day. The mean exit dose was 45.2 μg/day.
Remission rates:
- With lithium augmentation—15.9% by the HAM-D17, 13.2% by the QIDS-SR16
- With T3 augmentation—24.7% by both measures.
Response rates were 16.2% with lithium augmentation and 23.3% with T3 augmentation.
While neither response nor remission rates were statistically significantly different by treatment, lithium was more frequently associated with side effects (P = .045), and more participants in the lithium group left treatment because of side effects (23.2% vs 9.6%; P = .027). These results suggest that in cases in which a clinician is considering an augmentation trial, T3 has slight advantages over lithium in effectiveness and tolerability. T3 also offers the advantages of being easy to use and not necessitating blood level monitoring. These latter benefits are especially relevant to the primary care physician. However, T3’s potential for long-term side effects (eg, osteoporosis, cardiovascular effects) were not examined, and it is not clear when to discontinue it.
LEVEL 4: AFTER THREE FAILURES, HOW SHOULD A CLINICIAN PROCEED?
Switch to mirtazapine plus venlafaxine XR or tranylcypromine?
Patients who reached level 4 were considered to have a highly treatment-resistant depressive illness, so treatments at this level were, by design, more aggressive. Accordingly, at level 4 we investigated treatments that might be considered more demanding than those a primary care physician would use. Approximately 40% of patients in each treatment group were from primary care settings.
Remission rates40:
- With the combination of mirtazapine (mean dose 35.7 mg/day) and venlafaxine XR (mean dose 210.3 mg/day)—13.7% by the HAM-D17 and 15.7% by the QIDS-SR16
- With the MAOI tranylcypromine (Parnate, mean dose 36.9 mg/day)—6.9% by the HAM-D17 and 13.8% by the QIDS-SR16. Response rates were 23.5% with the combination and 12.1% with tranylcypromine. Neither remission nor response rates differed significantly.
However, the percentage reduction in QIDS-SR16 score between baseline and exit was greater with the combination than with tranylcypromine. Further, more patients dropped out of treatment with tranylcypromine because of side effects (P < .03). Tranylcypromine also has the disadvantage of necessitating dietary restrictions.
A significant limitation of this comparison is that patients were less likely to get an adequate trial of tranylcypromine, an MAOI, than of the combination. When the 2-week washout period (required before switching to an MAOI) is subtracted from the total time in treatment, approximately 30% of participants in the tranylcypromine group had less than 2 weeks of treatment, and nearly half had less than 6 weeks of treatment.
Therefore, even though the remission and response rates were similar between groups, the combination of venlafaxine-XR plus mirtazapine therapy might have some advantages over tranylcypromine. These results provided the first evidence of tolerability and at least modest efficacy of this combination for treatment-resistant cases.
Overall, what was the cumulative remission rate?
The theoretical cumulative remission rate after four acute treatment steps was 67%. Remission was more likely to occur during the first two levels of treatment than during the last two. The cumulative remission rates for the first four steps were:
- Level 1—33%
- Level 2—57%
- Level 3—63%
- Level 4—67%.
