Augmentation/Combination Therapy in the STAR*D Trial

More: Medscape Perspectives on the American Psychiatric Association (APA) 2007 Annual MeetingSelection from: Pharmacologic Management of Treatment-Refractory Depression

Augmentation/Combination Therapy in the STAR*D Trial  CME/CE

Maurizio Fava, MD   Jennifer M. Covino, MPA   Disclosures

According to the Global Burden of Disease Study,[1] the public health implications of depression are vast; depression currently ranks as the 4th leading global disease burden and is projected to rise to the number 2 disease burden worldwide in 2020, second only to ischemic heart disease. Antidepressants are the mainstay of treatment for depression and depressive episodes; however, these treatments are often incomplete or inadequate. Indeed, approximately 2 million individuals in the United States will experience an inadequate response to treatment for depression during their lives.[2] Clinicians are therefore presented with the challenge of tailoring and adjusting treatments to the individual patient, as they work to find the best matched treatment to not only achieve, but also to sustain remission.

In an effort to provide relief to those suffering from such a debilitating illness, clinicians rely on a variety of augmentation and combination strategies. New research presented at the 160th Annual Meeting of the American Psychiatric Association in San Diego, California, examined many of these strategies with a major focus on the recent Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

Treatment-Refractory Depression and STAR*D

The definition of treatment-refractory depression (TRD) is the subject of debate. TRD is described variously as depression that does not remit with 1 or more adequate antidepressant trials,[3] or 2 or more acute treatment trials;[4] or failure to respond to 4 or more different antidepressant approaches including augmentation, combination, and electroconvulsive therapy (ECT).[5] TRD can be related to a variety of factors including poor efficacy, intolerable adverse effects, drug-drug interactions, comorbid medical illness, and nonadherence.[6]

When considering the treatment of depression, one important limiting factor is the paucity of literature surrounding TRD, which is further complicated because published studies often have excluded many of the 'sickest' patients, precisely the patients that most clinicians face in daily practice.[7] The STAR*D study was designed to conduct research that mirrored clinical practice, providing options to patients seeking treatments as they moved through each step of the trial.[8]

The STAR*D project enrolled 4041 patients with a broad range of symptoms and severity from 25 participating sites.[9] The study involved 4 possible 'steps' for treatment, and any patient who failed to meet remission criteria at each step was then asked to move to the next level.[10] Of note, the study revealed what is often seen in clinical practice; patients tended to choose an option based on their experiences with the initial antidepressant. If they experienced a partial response, they chose augmentation; if they were not responding, they preferred to switch, and so forth.Level 1: The first treatment level consisted of citalopram at maximally tolerated doses titrated as quickly as could be achieved (dropout rate was approximately 8%). Patients were encouraged to continue the treatment for up to 12 weeks. A total of 3671 patients participated in level 1 treatment with citalopram monotherapy.

Level 2: After 12 weeks, if patients failed to reach remission in level 1, they were randomized to the next level, depending on their preference to switch to a different medication (bupropion SR, N = 239; sertraline, N = 238; or venlafaxine XR, N = 250), switch to cognitive therapy (N = 62), augment citalopram with another medication (bupropion SR, N = 279; or buspirone, N = 286), or augment citalopram with cognitive therapy (N = 85). Participants who chose to switch to or augment with cognitive therapy were randomized separately.

Level 3: Participants who did not achieve remission after 12 weeks in level 2 were randomized to: switch to mirtazapine (N = 110); switch to nortriptyline (N = 116); or augment level 2 treatment with lithium (N = 63) or thyroid medication (N = 70).

Level 4: To remain in the study, patients who did not achieve remission after 12 weeks in level 3 were required to switch to the nonhydrazine monoamine oxidase inhibitor, tranylcypromine (N = 55); or switch to a combination of venlafaxine XR and mirtazapine (N = 50).

This study used 3 methods of evaluation: HAM-D scales administered over the phone (single-blind) by those who did not know which treatment a patient was receiving; interactive voice response (IVR) system and self-reports with pencil; and paper Quick Inventory of Depressive Symptoms — self-report (QIDS) scale.

Augmentation and Combination in STAR*D

For purposes of this report, we will focus on the pharmacologic augmentation and combination results of those who remained on pharmacotherapy throughout the study.Level 2: Augmentation With Bupropion SR and Buspirone

Alan Schatzberg, MD, Professor of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California,[11] discussed some of the advantages and disadvantages of both bupropion SR and buspirone augmentation. First, Dr. Schatzberg noted that one advantage of bupropion SR is that it may assist with the treatment of SSRI-induced sexual dysfunction; but a disadvantage is that we lack double-blind placebo-controlled trials of bupropion, and the metabolism of this agent can inhibit metabolism of some SSRIs. By contrast, buspirone monotherapy has been studied in 5 double-blind trials with the composite data set showing efficacy; moreover, several open label trials have shown buspirone to be a useful augmentation agent. The largest disadvantage of buspirone augmentation is that this agent has generally failed in double-blind studies of refractory depression.

Dr. Schatzberg, specifically discussed the resulting data from the STAR*D level 2 treatment arm that involved augmentation with sustained release bupropion (up to 400 mg/day; N = 279) or buspirone (up to 60 mg/day; N = 286). Remission rates based on the Hamilton Rating Scale for Depression (HRSD-17) were 29.7% for bupropion and 30.1% for buspirone. Remission rates based on QIDS-SR-16 were 39.0% for bupropion and 32.9% for buspirone.

Trivedi and colleagues[12] evaluated the use of bupropion and buspirone in the STAR*D study and found that bupropion led to greater reduction in the number and severity of symptoms, with fewer side effects and adverse events. In this analysis, the group that received sustained-release bupropion demonstrated greater reductions in QIDS-SR-16 scores than buspirone (25.3% vs 17.1% from baseline, P < .04); a lower QIDS-SR-16 score (8.0 vs 9.1, P < .02); and lower dropout rates related to intolerance (12.5% vs 20.6%, P < .009).Level 3: Lithium and Triiodothyronine Augmentation

Dr. Schatzberg also discussed lithium and thyroid augmentation.[11] He began by summarizing the highlights of the literature on lithium. At least 50 trials have used lithium as an augmentation agent and yielded mostly positive results; these studies have most frequently used lithium in conjunction with tricyclic antidepressants; levels of 0.4 mg to 0.6 mg are often effective; there is a low therapeutic index; and patients sometimes require monitoring of thyroid and renal function, an additional burden. With regard to augmentation with thyroid hormone, there have been at least 25 mostly positive trials; studies have indicated that thyroid augmentation may help with energy and weight; it is well tolerated when compared with lithium; it may work less well in men; it can cause bone demineralization; and thyroid levels must be monitored, adding a burden to patients.

Timothy Petersen, PhD,[13] Assistant Professor of Psychiatry at Harvard Medical School in Cambridge, Massachusetts, summarized the level 3 augmentation options of either lithium (N = 69) or T3 (N = 73). Based on HRSD-17, remission rates were 15.9% for lithium and 24.7% for T3; based on the QIDS-SR-16, remission rates were 13.2% for lithium and 24.7% for T3. These results indicate that failure to achieve response or remission at level 2 (bupropion SR or buspirone) predicts lower response/remission rates at level 3. Despite the low numbers, a limited number of patients will experience benefit with lithium or T3, indicating that using all available options is sometimes necessary because we currently cannot predict who might respond to which medication and/or augmentation strategy.

STAR*D Augmentation/Combination Summary

Dr. Petersen[13] concluded that when one looks at the STAR*D, data pertaining to remission based on the augmentation/combination trials (levels 2-4), one sees that remission rates drop from 35% at level 2 to 19% at level 3 and 16% at level 4, which, according to Dr. Petersen, indicates that failure to achieve remission with one agent at level 1 does not substantially reduce the chances of remission with a next-step augmentation trial. However, failure to achieve remission with 2 consecutive treatments is associated with very low remission rates with subsequent treatments. Dr. Shatzberg[11] concluded that although remission rates were relatively low in all phases, buspirone, bupropion SR, and thyroid appear to offer considerable benefit. He also noted that low remission rates across all trials indicate that many patients still require additional treatment.

The STAR*D trial was designed to mirror the methods clinicians use in practice, and the results of this large multicenter trial mirror what many clinicians have seen for years — challenges in understanding and deciding upon the best treatment options for the individual patient in an effort to achieve and maintain response with the ultimate goal of remission. STAR*D shows that, as additional augmentation/combination strategies are used, the response and remission rates of patients decreased; however, a small population of patients did respond and/or remit with these additional strategies. Thus, clinicians must use an array of pharmacotherapies as they work to alleviate depression in patients through what becomes an individualized 'trial and error' mechanism. Of importance, the STAR*D study also highlights that despite our best efforts, and given our current treatment options, a vast number of individuals remain without relief from their depression. Clearly further research is warranted as we work to understand the underlying causes of depression and best treatment modalities for individuals suffering from this illness.

Supported by an independent educational grant from Bristol-Myers Squibb

References

References

Murray CJL, Lopez AD. Alternate projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349:1498-1504. AbstractNemeroff CB. Caring for our most challenging patients with depression: an interactive forum on novel treatments. Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 17B.Fava M, Davidson KG. Definition and epidemiology of treatment-resistant depression. Psychiatr Clin North Am. 1996;19:179-200. AbstractRush A. Treatments after the first two steps including follow-up: level 3 and level 4. Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 21D.Nemeroff CB. Caring for our most challenging patients with depression: an interactive forum on novel treatments. Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 17B.Perlis RH. Do antidepressants work in the real world and for whom? Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 4B.Alpert JE. Improving depression treatments: bridging the gap between clinical trials and community practice. Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 28A.Fava M. Insights from STAR*D: are our patients' needs being met? Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 4A.Nierenberg AA. A critique of current and future treatments for difficult-to-treat depression. Program and abstracts of the American Psychiatric Association 158th Annual Meeting; May 21-26, 2005; Atlanta, Georgia. Abstract 86C.Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917. AbstractSchatzberg AF. Augmentation and combination strategies in treatment resistant depression. Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 4E.Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354:1243-1252. AbstractPetersen T. The sequenced treatment alternatives to relieve depression (STAR*D) study: lessons learned. Program and Abstracts of the American Psychiatric Association 160th Annual Meeting; May 19-24, 2007; San Diego, California. Abstract 28F.
  
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