STAR*D: Some Treatment-Resistant Depression Responds to Change in Drug Regimen

Nothing better reflects the difficulties of finding silver bullets for depression treatment than the results of the nearly completed Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest clinical trial of its kind. With results imminent from the last of 4 trials in the study, psychiatrists are hoping for considerably more clinical guidance than what the first 3 levels of the trials produced.

The STAR*'D study has been trying to glean insights on the best way to treat chronically depressed patients who do not respond to a first, then a second, and then a third treatment. The study has focused on the outcome of remission, not-as is typical in drug company trials-a simple improvement in condition. The results of the first 3 levels have been published, with the fourth level's results expected to hit the press before the end of 2006.

Matthew Menza, MD, professor and vice chair, department of psychiatry, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, noted in an interview with Psychiatric Times that about 65% to 70% of the participants who stayed in the trial (4000 started at level 1) found significant relief, meaning that they experienced remission. "This is consistent with what we see in clinical practice," he explained. "If people stay in treatment, most people in the end get very significant relief, but it takes a lot of time and effort. This message should not get lost."

Looked at another way, though, the results are less impressive. For those participants who did not experience re mission with the first drug and agreed to continue to the next level, the chance of achieving remission was about 20%. "The results of STAR*D continue to be sobering," stated Robert Freedman, MD, editor-in-chief of The American Journal of Psychiatry. "By the third wave of the study, the rate of remission continues to be quite low, which underscores the persistence of depression and its resistance to current treatments."

Freedman, professor and chairman of the department of psychiatry at the University of Colorado at Denver and Health Sciences Center, explained in an interview that the hope going into STAR*D was that some secondary treatments "would clearly emerge as winners." That did not happen. "We learned [that] secondary treatments certainly help substantial numbers of people," Freedman continued, "but all of them have limited effects. That is what is sobering."

Moreover, citalopram (Celexa), a front-line treatment that was given to all 4000 participants who started out in level 1, "was not as effective as we had hoped," according to Freedman.

Menza acknowledged that even the 65% to 70% remission rate was open to question. STAR*D investigators have not gone back and studied those who experienced remission in level 1 to see if they had subsequent episodes of depression. Compiling that data might reduce the initial cited success rate, he pointed out.

Nonetheless, one thing that STAR*D has proved is that a broad range of patients outside of academic hospitals react in about the same way to various psychiatric drugs as do those in academic hospitals. That is important because drug company clinical trials have been conducted almost exclusively in academic centers. Clinicians have wondered whether patients whom they see in their office, who may have less debilitating depression and who may span a broader range of groups, would react to medications in the same way as the selected patients who typically form clinical trial groups. STAR*D included minorities and patients with comorbidities, for example. "It is comforting to know [that] these individuals did as well as the participants who are typically in our studies," Menza added.

So STAR*D seems to have been more significant for its structure, com position, and parameters than for its results. Administered by the National Institute of Mental Health, which, according to Menza, budgeted about $35 million (drug companies donated the medicines), the study started at level 1 with 4000 patients, far more than the 300 to 500 participants who are typically enrolled in drug company-sponsored clinical trials aimed at learning the efficacy and safety of new drugs prior to the submission of a new drug application to the FDA.

Patients at level 1 were given citalopram, an SSRI, for up to 14 weeks. If the patient did not experience remission, he or she was given the option of continuing to level 2; 1439 participants accepted. Fifty-one percent (727) of these patients chose options that in cluded switching to a different med ication and were randomly assigned to receive sertraline (Zoloft), sustained-release bupropion (Wellbutrin), or extended-release venlafaxine (Effexor); 39% (565) chose options that included augmenting the citalopram they were already taking and were randomly assigned to drug therapy with sustained-release bupropion or buspi rone (Buspar). In level 3, 114 patients who were still depressed were randomly as signed to receive mirtazapine (Remeron) and 121 to receive nortrip tyline (Aventyl, Pamelor) for up to 14 weeks of treatment.

The first 3 levels have produced some insights, although nothing earth-shattering. A. John Rush, MD, of the University of Texas Southwestern Medical Center at Dallas, highlighted the fact that some patients experienced remission with an SSRI in level 2 after getting no relief from citalopram in level 1. "Contrary to what previous research suggests, this study shows that all 3 medications the patients switched to (in level 2), despite having different mechanisms of action, appear to be useful options for treating depression following failure [of] the first SSRI," said Rush, one of the principal investigators for the study. "The results provide patients and doctors with important information-that intolerance or lack of efficacy with one SSRI seems not to predict the same with another."

Referring to the results of level 2, Menza said the results from the 2 groups of patients did not differ significantly. "We are left wondering whether the difference was mere chance or if we really should be using tricyclic antidepressants, such as nortriptyline, more than we currently do."

In an editorial he wrote for the July issue of The American Journal of Psychiatry, Menza sounded some cautionary notes. "This first wave of data from STAR*D will not greatly affect the prescribing practices of most clinicians," he wrote. "While it is asking too much of any study, we are left wanting more-more attention to other current options, more certainty, and in the end, more guidance."