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Third Medication Can Be The Charm for Depression

  [ 357 votes ]   [ Discuss This Article ]
By Editor • • July 18, 2006

Even after failing to find relief of symptoms following two sequential trials of differently acting antidepressant drugs, clinically depressed outpatients who persevere through a third round still have a “moderate chance” of becoming symptom free and “should not give up.” That’s the word from a landmark $35 million National Institutes of Health study involving 2,876 subjects seen in clinics nationwide – the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Nearly half of all patients became symptom-free in the first and second rounds. And of those who opted to try a third round, as many as 20 percent achieved symptom remission. But more important, data on all these cases should improve future first-prescription success rates, by sharpening the science behind prescribing protocols. This is especially significant for Fibromyalgia patients, who are more than three times more likely than those without FM to be diagnosed with depression, and for CFS patients, who may be as much as seven times more likely to suffer episodes of depression, according to national Canadian health surveys.1 The primary purpose of STAR*D was “to determine which treatments work best if the first treatment with medication does not produce an acceptable response.” It took patients, who could opt out at any stage, through several rounds of prescribed drug therapies. These were in line with the current “real-world” sequence of drugs in different pharmacological classes that physicians seeing depressed patients will typically try. Key study findings are that:
  1. About one-third of the depressed patients achieved essential remission of symptoms during trial of the first-round SSRI medication.2 The starter drug, citalopram (sold under the brand name Celexa) is a widely used “selective serotonin reuptake inhibitor.” Drugs in the relatively new SSRI class of antidepressants act to hinder reabsorption of the neurotransporter serotonin, thus concentrating this brain cell-impulse stimulator.
  2. About one-fourth of the 790 patients who agreed to proceed to a non-SSRI in round two achieved remission.3 Success rates were roughly equivalent with the three randomly assigned alternative non-SSRI medications. These were bupropion sustained-release (also known as Wellbutrin and Zyban), sertralene (Zoloft), and venlafaxine (Effexor) extended-release, which has been described as a “multi-purpose” drug for Fibromyalgia patients in that it may address depression, anxiety, sleep, and pain.
  3. Non-SSRIs, which differ from each other, inhibit reuptake of various neurotransporters – potentially including serotonin, but also others such as dopamine, which is similar to adrenaline, or the stress hormone norepinephrine. Hence the “selectivity” of the SSRIs.
  4. As many as 20 percent of the 235 patients who hung in for trial of a third-round “cyclic” drug achieved remission. The patients were randomly assigned to receive either the tetracyclic mirtazapine (Remeron), or the tricyclic nortriptyline (Aventyl or Pamelor). Neither drug demonstrated a clear advantage over the other.4 Cyclics are an older class of antidepressants that work to “beef up” norepinephrine and serotonin, but tend to have more side effects than subsequent drug generations, including particularly fatigue and dry mouth. They came into use in the 1950s, and are generally used with patients who haven’t responded to other medications.

More-Tailored Protocols Ahead

The STAR*D researchers collected highly detailed data and DNA samples for all these patients – a truly representative sample of the nation’s 14.8 million annual depression cases. The correlations they identify between symptoms, patient characteristics and health conditions, and drug efficacy should shed considerable light on what works for whom. A still-forthcoming STAR*D report will examine results achieved for a fourth group of patients that branched off from the “sequenced alternatives” plan: those who did not achieve remission in round one or round two, but opted to continue with and augment their current medication based on a positive response. Together, those who had a significant positive response and those who achieved remission in round one represented 47 percent of the entire study group. Psychopharmacology expert Matthew Menza, MD, director of the anxiety disorders program at Robert Wood Johnson University Hospital, suggests that patients in this fourth STAR*D group who switched from one SSRI to another may have had similar or better chances of remission than those who went on to try a non-SSRI or cyclic drug. 5


  1. Go to the library for abstracts of “Long-term medical conditions and major depression: Strength of association for specific conditions in the general population,” by Scott Patten, et al., from the March 2005 issue of the Canadian Journal of Psychiatry, and “Major depression, fibromyalgia and labour force participation: A population-based cross-sectional study,” by Aliya Kassam and Scott Patten, from the January 2006 issue of BMC Musculoskeletal Disorders.
  2. “Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice” Madhukar Trivedi, MD, et al., American Journal of Psychiatry, January 2006.
  3. “Bupropion-SR, Sertraline, or Venlafaxine-XR after Failure of SSRIs for Depression,” by A. John Rush, MD, et al., New England Journal of Medicine, March 23, 2006.
  4. “A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments: A STAR*D report,” by Maurizio Fava, MD, et al., American Journal of Psychiatry, July 2006.
  5. “STAR*D: The results begin to roll in,” by Matthew Menza, MD, The American Journal of Psychiatry, July 2006.

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