In spite of the variety of medication options now available, major depression remains a challenging disease to treat. Only about half of adult patients respond to the first antidepressant prescribed, with only one-third achieving remission.
When symptoms are not adequately relieved by the first antidepressant, patients and their clinicians face a difficult decision. Although two broad strategies exist—switching to a new drug or augmenting the first drug with a second—it hasn't been clear which strategy is best. Most of the research has been on initial treatment, pitting a new drug against an old one. Studies evaluating medication augmentation or switching strategies have usually been short-term and compared a drug to a placebo, rather than to another drug.
Over the past few years, two separate streams of research in adults have helped fill this gap in knowledge. One is the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, the largest prospective study of successive treatment options ever conducted. The study enrolled 3,671 patients at 41 sites nationwide (23 psychiatric clinics and 18 primary care clinics). The design was intended to mimic real-world practice, where nearly half of patients with major depression receive their care from primary care physicians, and where the first treatment offered may not work.
STAR*D results indicate that—with persistent trial and error to find the right medication—nearly seven in 10 adult patients with major depression will eventually find a treatment that works (see table). However, the study also made clear what many clinicians and patients know from experience: remission becomes much harder to achieve after two medication trials have failed.
Although new antidepressants are in development, the drug testing process takes years. A second and quite active area of research, therefore, is aimed at identifying new ways to augment medications already available to make them more effective.
STAR*D design and outcomes Patients progressed from one level to the next if their symptoms were not adequately relieved after 14 weeks of a particular treatment. | |||
Study arm | Treatment options | Cumulative remission rates | |
Level 1 | Citalopram (Celexa) | 33 percent | |
Level 2 | Switch to bupropion (Wellbutrin), sertraline (Zoloft), venlafaxine (Effexor), or cognitive therapy | Augment citalopram with bupropion, buspirone (BuSpar), or cognitive therapy | 57 percent |
Level 3 | Stop current therapy and switch to mirtazapine (Remeron) or nortriptyline (Pamelor) | Augment current therapy with lithium or T3 thyroid hormone (Cytomel) | 63 percent |
Level 4 | Stop current therapy and receive tranylcypromine (Parnate) or mirtazapine plus venlafaxine | 67 percent | |
Initial considerations
When patients do not benefit adequately from a first medication, taken as prescribed, it's wise to do the following before deciding on the next treatment.
Review symptoms and diagnosis. Major depression can be difficult to diagnose because symptoms vary and may also overlap with those of other psychiatric disorders. A common challenge, for instance, is distinguishing major depression from bipolar disorder, yet this distinction significantly influences treatment choices. Patients with bipolar disorder typically don't respond to antidepressants alone, and instead require a mood stabilizer to alleviate symptoms. In addition, major depression frequently occurs in conjunction with other disorders, such as anxiety, which can also affect medication choice and response.
Give it more time. Although the standard advice is for patients to take a medication for six weeks to see if symptoms improve, the STAR*D trial suggests that many patients need more time to respond. All patients in the study initially received citalopram (Celexa), a selective serotonin reuptake inhibitor (SSRI). Half of the patients who reached remission did so after six weeks; some needed as long as 12 or 14 weeks. As a result, the investigators recommended that patients take an initial drug for at least eight weeks. They also recommended that patients complete self-report instruments such as the 16-item Quick Inventory of Depressive Symptomatology (available free, along with other instruments for clinicians, at www.ids-qids.org) to monitor progress and side effects.
Consider options. Many choices are available if a depression treatment fails to relieve symptoms. In STAR*D, none of the options was a clear winner. And patients could choose to switch drugs or augment them at critical junctures, so it remains unknown whether it's better to augment antidepressants that are providing only partial relief or switch to new ones. Even so, the study provides new information about how likely it is that a patient will achieve remission after a previous drug fails.
Summary points
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